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Altered Expression of Two-Pore Domain Potassium (K2P) Channels in Cancer

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Potassium channels have become a focus in cancer biology as they play roles in cell behaviours associated with cancer progression, including proliferation, migration and apoptosis. Two-pore domain (K2P) potassium channels are background channels which enable the leak of potassium ions from cells. As these channels are open at rest they have a profound effect on cellular membrane potential and subsequently the electrical activity and behaviour of cells in which they are expressed. The K2P family of channels has 15 mammalian members and already 4 members of this family (K2P2.1, K2P3.1, K2P9.1, K2P5.1) have been implicated in cancer. Here we examine the expression of all 15 members of the K2P family of channels in a range of cancer types. This was achieved using the online cancer microarray database, Oncomine (www.oncomine.org). Each gene was examined across 20 cancer types, comparing mRNA expression in cancer to normal tissue. This analysis revealed all but 3 K2P family members (K2P4.1, K2P16.1, K2P18.1) show altered expression in cancer. Overexpression of K2P channels was observed in a range of cancers including breast, leukaemia and lung while more cancers (brain, colorectal, gastrointestinal, kidney, lung, melanoma, oesophageal) showed underexpression of one or more channels. K2P1.1, K2P3.1, K2P12.1, were overexpressed in a range of cancers. While K2P1.1, K2P3.1, K2P5.1, K2P6.1, K2P7.1 and K2P10.1 showed significant underexpression across the cancer types examined. This analysis supports the view that specific K2P channels may play a role in cancer biology. Their altered expression together with their ability to impact the function of other ion channels and their sensitivity to environmental stimuli (pO2, pH, glucose, stretch) makes understanding the role these channels play in cancer of key importance.
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Altered Expression of Two-Pore Domain Potassium (K
2P
)
Channels in Cancer
Sarah Williams
1
, Andrew Bateman
2
, Ita O’Kelly
1
*
1Human Development and Health, Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, United
Kingdom, 2Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
Abstract
Potassium channels have become a focus in cancer biology as they play roles in cell behaviours associated with cancer
progression, including proliferation, migration and apoptosis. Two-pore domain (K
2P
) potassium channels are background
channels which enable the leak of potassium ions from cells. As these channels are open at rest they have a profound effect
on cellular membrane potential and subsequently the electrical activity and behaviour of cells in which they are expressed.
The K
2P
family of channels has 15 mammalian members and already 4 members of this family (K
2P
2.1, K
2P
3.1, K
2P
9.1, K
2P
5.1)
have been implicated in cancer. Here we examine the expression of all 15 members of the K
2P
family of channels in a range
of cancer types. This was achieved using the online cancer microarray database, Oncomine (www.oncomine.org). Each gene
was examined across 20 cancer types, comparing mRNA expression in cancer to normal tissue. This analysis revealed all but
3K
2P
family members (K
2P
4.1, K
2P
16.1, K
2P
18.1) show altered expression in cancer. Overexpression of K
2P
channels was
observed in a range of cancers including breast, leukaemia and lung while more cancers (brain, colorectal, gastrointestinal,
kidney, lung, melanoma, oesophageal) showed underexpression of one or more channels. K
2P
1.1, K
2P
3.1, K
2P
12.1, were
overexpressed in a range of cancers. While K
2P
1.1, K
2P
3.1, K
2P
5.1, K
2P
6.1, K
2P
7.1 and K
2P
10.1 showed significant
underexpression across the cancer types examined. This analysis supports the view that specific K
2P
channels may play a
role in cancer biology. Their altered expression together with their ability to impact the function of other ion channels and
their sensitivity to environmental stimuli (pO2, pH, glucose, stretch) makes understanding the role these channels play in
cancer of key importance.
Citation: Williams S, Bateman A, O’Kelly I (2013) Altered Expression of Two-Pore Domain Potassium (K
2P
) Channels in Cancer. PLoS ONE 8(10): e74589.
doi:10.1371/journal.pone.0074589
Editor: Sven G. Meuth, University of Muenster, Germany
Received June 3, 2013; Accepted August 3, 2013; Published October , 2013
Copyright: ß2013 Williams et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Work funded by the Gerald Kerkut Charitable Trust (http://www.southampton.ac.uk/,gktrust/). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: I.M.O’Kelly@southampton.ac.uk
Introduction
Traditionally, the study of ion channels has focused on their
roles in excitatory cells (neuronal, cardiac and secretory), however
more recently, ion channels have been recognised for their roles in
the behaviours of cancer cells and the development and
progression of cancer. In the last 15 years increasing evidence
supports the role of ion channels in mitogenesis, the control of
cellular proliferation and apoptosis as well as cell migration and
metastasis [1–8]. Overexpression of some ion channels has been
linked to poor prognosis [9] while other channels are now
recognised as potential biomarkers for particular cancer types
[10,11]. These reports, together with the potential of targeting ion
channel function through pharmacological modulation, make
understanding the role of ion channels in cancer biology of key
importance.
K
+
channels play fundamental roles in cell behaviours linked to
cancer progression, including regulation of cell proliferation,
migration, apoptosis and angiogenesis [2,12–14]. Cell membrane
potential (driven by K
+
channel activity) plays an important
regulatory role in cell cycle progression and proliferation, with
highly proliferating cells displaying a more positive membrane
potential than quiescent cells, while a transient membrane
hyperpolarisation enables G1 progression [15–18]. The precise
regulatory mechanisms are unclear but evidence supports two
hypotheses. The first proposes that changes in membrane potential
due to K
+
channel activity modulates voltage-gated Ca
2+
channels,
thus impacting Ca
2+
influx and downstream signalling [17,19].
The alternative hypothesis proposes that the changes in cell
volume seen during proliferation (cell swelling) and apoptosis (cell
shrinkage) may be regulated by K
+
channel activity [18,20,21]. In
a similar manner, K
+
channel control of membrane potential has
been shown to impact cell migration through regulation of cell
volume, pH and intracellular Ca
2+
concentration. A direct impact
of alteration in membrane potential on cytoskeletal polymerisation
has also been demonstrated [14,22,23].
Altered K
+
channel expression and/or function occurs in a
range of cancer types, with ion channels from each of the K
+
channel families (voltage sensitive (K
V
); calcium sensitive (K
Ca
);
inwardly rectifying (K
ir
); and two-pore domain (K
2P
) channels)
implicated in cancer development and progression. Within the K
V
family, K
V
11.1 (hERG) shows altered expression in an array of
cancer types and has been shown to impact cellular proliferation
(melanoma, colorectal cancer and Barrett’s esophagus), migration
(melanoma, thyroid and breast cancer), malignant transformation
(head & neck carcinoma) and apoptosis (gastric cancer). While
K
V
11.1 is most frequently reported for its role in cancer, an array
of other K
+
channels have also been proposed as molecular
PLOS ONE | www.plosone.org 1 October 2013 | Volume 8 | Issue 10 | e74589
7
components promoting cancer development and progression
[9,10,24–80] (summarised in Table 1).
The potential role of K
2P
channels in cancer is of particular
interest. These channels conduct outward K
+
background currents
and are active at resting membrane potentials, thus they have a
direct influence on baseline cellular activity of cells at rest
including membrane potential, calcium homeostasis and cell
volume regulation. K
2P
channels also show sensitivity to physio-
logical stimuli including pH, oxygen tension, glucose concentra-
tion and stretch; key physiological parameters which are disrupted
within the cancer cells and their environment [81–83].
Of the 15 mammalian K
2P
family members, four K
2P
channels
(K
2P
2.1 (TREK-1), K
2P
3.1 (TASK-1), K
2P
9.1 (TASK-3) and
K
2P
5.1 (TASK-2)) have already been implicated in cancer. In
2003, Mu et al. [77] described KCNK9, the gene encoding K
2P
9.1,
as a potential proto-oncogene where genomic overexpression of
the gene was detected in 10% of breast carcinomas and the protein
was detected in 44% of breast tumours by immunohistochemistry
but not in normal tissue controls. The oncogenic ability (measured
by proliferative advantage) was demonstrated to depend upon a
functional channel [84]. K
2P
9.1 immunopositivity has subsequent-
ly been reported in colorectal carcinomas [78] and melanoma
tissue samples [85].
Increased K
2P
2.1 expression was detected in prostate adeno-
carcinoma samples compared to normal prostate epithelium and
reduced proliferation of prostate cancer cell lines was observed
when K
2P
2.1 was experimentally knocked down [74].
A study by Nogueira et al. (2010) [75] linked K
2P
3.1 expression
to aldosterone production in both aldosterone-producing adeno-
mas and normal adrenals, and proposed K
2P
3.1 may play a role in
Ca
2+
signalling regulation. Equally, K
2P
3.1 and K
2P
9.1 have
previously been reported to play a role in K
+
-dependent apoptosis
in granule cell neurons in culture [86].
Transcriptome analysis in human ductal breast epithelial
tumour cell line, T47D, following either stimulation with either
estrogen receptor (ER) awhich induces proliferation or ERb
which has antiproliferative effects showed that K
2P
5.1 mRNA was
upregulated by ERasignalling [87]. mRNA, protein and
functional expression (acid-sensitive outward currents) of K
2P
5.1
was reported to increase in response to 17b-estradiol stimulation of
ERasignalling in T47D and human breast adenocarcinoma cell
line, MCF-7. While experimental knockdown of K
2P
5.1 moder-
ately reduced basal proliferation of T47D cells, a significantly
greater reduction in estrogen-induced proliferation was observed
[76].
Evidence from these studies supports the hypothesis that
alterations to the expression or function of K
2P
channels in cancer
cells may play a role in cancer development and progression.
Targeting these channels may lead to novel cancer therapies; we
therefore sought to determine the transcript expression of each of
the K
2P
channels in a range of cancers using an online cancer
microarray database, Oncomine (www.oncomine.org, Compendia
biosciences, Ann Arbor, MI, USA). This information documents
changes in the expression of the K
2P
family members in a range of
cancer types and provides a valuable resource to enable further
Table 1. Summary of potassium channel expression in cancer.
Channel Expression detected Behavioural impact Ref
K
V
1.3 Breast, lung, lymphoma, pancreatic, prostate Apoptosis, poor prognosis, proliferation [24–28]
K
V
1.4 Gastrointestinal Gene silencing [29]
K
V
1.5 Brain Increased survival [30]
K
V
3.4 Head and neck Proliferation [31]
K
V
4.1 Breast, gastrointestinal Proliferation [32,33]
K
V
10.1 Bone, breast, cervical, colorectal, esophageal, head and neck,
kidney, leukemia (acute myeloid), ovarian
Biomarker, migration, proliferation, poor prognosis [10,34–42]
K
V
10.2 Brain, kidney Proliferation [42,43]
K
V
11.1 Breast, colorectal, esophageal, gastrointestinal, head and neck,
kidney, leukemia (acute myeloid), lung, melanoma, ovarian,
retinoblastoma, thyroid
Migration, proliferation, poor prognosis, [22,34,36,42,44–
49]
K
Ca
1.1 Bone, brain, breast, ovarian, prostate Apoptosis, metastases, microenvironment regulation,
migration, proliferation
[9,50–55]
K
Ca
2.3 Breast, colon, melanoma Migration [56–58]
K
Ca
3.1 Brain, breast, colorectal, melanoma, prostate Migration, proliferation [59–63]
K
ir
2.2 Breast, gastrointestinal, prostate Cell cycle [64]
K
ir
3.1 Breast, lung, pancreatic Metastases, proliferation [27,65,66]
K
ir
3.4 Aldosterone-producing adenomas Mutations detected [67]
Kir4.1 Brain Migration, poor prognosis [68,69]
K
ir
6.1/K
ir
6.2 Brain, breast, melanoma, uterine Apoptosis, cell cycle, proliferation [70–73]
K
2P
2.1 Prostate Proliferation [74]
K
2P
3.1 Aldosterone-producing adenomas Aldosterone production [75]
K
2P
5.1 Breast Proliferation [76]
K
2P
9.1 Breast, colorectal, lung, melanoma Apoptosis, migration, mitochondrial function, proliferation [77–80]
Potassium channels identified in specific cancer types together with the predominant behavioural characteristics. Channels are divided into family groups, voltage-
gated (K
V
), calcium-gated (K
Ca
), inward rectifying (K
ir
) and two-pore domain (K
2P
).
doi:10.1371/journal.pone.0074589.t001
K
2P
Channel Expression in Cancer
PLOS ONE | www.plosone.org 2 October 2013 | Volume 8 | Issue 10 | e74589
investigation into the protein expression and potential roles of
these important channels in cancer progression.
Methods
Analysis of KCNK mRNA expression in cancer tissue samples
(meta-analysis of KCNK genes and related statistical analyses)
were performed using the online cancer microarray database,
Oncomine (www.oncomine.org, Compendia biosciences, Ann
Arbor, MI, USA). Oncomine collects publicly available cancer
microarray data and processes all data imposing the same criteria
[88]. The mRNA expression data is organised into cancer types
defined within the original publications. mRNA expression data
was extracted from Oncomine between August 2012 and January
2013. Citations for all primary studies used together with
information on cancer type and staging (where available) is
provided in Table S1 in File S1.
Only datasets examining KCNK gene mRNA expression in
cancer tissue which was matched with normal tissue controls
(cancer vs. normal) were included in this study. Threshold criteria
had to be achieved by each study for inclusion in the analysis. The
threshold search criteria used for this study were a p-value,0.05, a
fold change .2 and a gene rank percentile ,10%. P-values
presented in this study for differential expression analysis of
KCNK genes were calculate by Oncomine using a two-sided
Student’s t-test and multiple testing correction [86,87]. Multiple
testing correction was performed using the false discovery rate
method, where corrected p-values (Q-values) were calculated as
Q = NP/R (where P = p-value, N = total number of genes and R is
the sorted rank of p-value) [88,89]. In this study a p-value less than
0.05 was considered significant. Fold change is defined as the
linear change in mRNA for the gene of interest in cancer tissue
when compared to the normal expression level for that tissue, in
this case a fold change of 2 and greater was included for analysis.
For each dataset the genes studied are ranked by their p-value.
The gene rank percentile is the percentage ranking of the gene of
interest compared to all other genes analysed in that dataset based
on p-values. The average number of genes examined in the
microarray data presented in this study was approximately 14,000
genes. Datasets in which the gene of interest was in the top 10% of
genes changed were included. These threshold values are
connected by the Boolean AND, therefore an analysis was only
classed as above threshold when it met all three criteria.
Initially KCNK genes (KCNK1–18) were examined across a
range of 20 cancer types, which have been grouped by their tissue
of origin (Table S2 in File S1), comparing mRNA expression in
that cancer type to normal tissue controls. Gene summary view in
Oncomine was utilised during this analysis and presented here
with expression ranking indicated by colour shading. Expression
colouring for a gene in a particular cancer relates to the gene rank
percentile for the highest ranking above threshold analysis.
Further analysis was performed on each KCNK gene, for
expression in the most prevalent cancer types based on
GLOBACON 2008 WHO rankings (http://globocan.iarc.fr/)
[90]. Lymphoma, myeloma, sarcoma, liver and ovarian cancers
were removed from further analysis due to low KCNK expression.
The subtype ‘other cancers’ which is defined as cancers which do
not fall into the prescribed subtypes (e.g. uterine and adrenal
cancers) was also removed from further analysis as the large
diversity of cancer subtypes within this group would make detailed
analysis uninformative. Using the threshold criteria described
previously all above threshold analyses for each KCNK gene was
extracted from Oncomine and complied.
Once all above threshold data for each KCNK gene had been
complied, comparative meta-analysis was performed on cancer
subtype with more than five datasets (n$5) available, this analysis
provided a median gene rank and median p-value for that cancer
subtype.
Results and Discussion
KCNK genes show altered expression across different
cancers
KCNK genes 1–18 (with the omission of KCNK8, KCNK14
and KCNK11 which were ascribed proteins but subsequently
withdrawn due to nomenclature duplication) encode the mam-
malian family of K
2P
channels [91]. Initially to obtain a global
view of changes in K
2P
channel expression in cancer, we used the
Oncomine cancer microarray database to analyse the alterations
observed in KCNK gene mRNA expression in the 20 most
commonly diagnosed cancers, grouped by their tissue of origin,
compared to normal tissue controls. For inclusion in the analysis,
changes in gene expression compared to normal controls had to
fulfil threshold criteria of achieving a p-value,0.05, a fold change
.2 and a gene rank percentile ,10%. The gene rank percentile
values for each of the 15 KCNK genes in cancers compared to
normal tissue controls were examined and the percentile of the
highest ranking analyses are shown for each KCNK gene and each
cancer tissue type in Figure 1. Performing analysis in this way
enabled comparison of alterations in gene expression to be
performed between different microarray experiments and revealed
that all KCNK genes with the exception of KCNK4 (K
2P
4.1 or
TRAAK), KCNK16 (K
2P
16.1 or TALK1) and KCNK18
(K
2P
18.1 or TRESK) show altered expression in the 20 cancer
types examined when compared to normal tissue controls
(Figure 1A & B). Cancers from fourteen tissue types showed
over-expression of more than one KCNK gene (Figure 1A) with
five cancer tissue types (breast, kidney, leukaemia, lung, lympho-
ma) showing over-expression of three or more KCNK genes
(Figure 1A). While broad cancer tissue types are considered in this
initial analysis and include a range of different cancer diseases,
they provide valuable preliminary information on the expression
of KCNK genes in cancer and further analysis taking into account
specific cancer subtypes (e.g. acute versus chronic leukaemia) was
performed for specific channels in subsequent analyses.
When examining underexpression of KCNK genes, cancer
from 19 of the 20 tissue types analysed showed decreased
expression of one or more KCNK genes when compared to
normal tissue expression (Figure 1B). Six K
2P
family members
(KCNK1, KCNK2, KCNK3, KCNK5, KCNK7 and KCNK10)
show underexpression in over 5 different cancer tissue types of
(Figure 1B). While 10 different cancer tissue types (brain, breast,
colorectal, gastrointestinal, head and neck, kidney, lung, melano-
ma, prostate and sarcoma) show underexpression of at least three
KCNK genes (Figure 1B). Strikingly, specific K
2P
channels show
increased mRNA expression in some cancer tissues while
decreased expression in others. This is particularly apparent for
KCNK1, KCNK3, KCNK5 and KCNK6, which displayed
mRNA expression changes (either up or down in distinct cancers)
which rank them in the top 1% of genes showing altered
expression for those cancers. KCNK1, for example, is in the top
1% of genes showing overexpression in bladder, cervical, lung and
pancreatic cancers, while in cancers of the central nervous system
KCNK1 shows one of the highest reductions in expression when
compared to normal tissue controls (Table 2). These analyses
suggest that the impact of down-regulation of K
2P
channels on cell
K
2P
Channel Expression in Cancer
PLOS ONE | www.plosone.org 3 October 2013 | Volume 8 | Issue 10 | e74589
function may be an equally important alteration as increased
expression in cancer biology.
KCNK expression in specific cancer types
The 15 members of the K
2P
channel family are divided into 6
separate groupings on the basis of their sequence homology and
defining biophysical characteristics. The expression of each gene
in each of the 14 cancer tissue types (6 tissues were excluded from
this analysis due to low dataset numbers or high cancer subtype
diversity) was studied in detail using the analysis threshold values
as before (p-value,0.05, fold change .2 and gene rank percentile
,10%) and the results are presented for each channel group
(Tables 2, 3, 4, 5, 6 & Table S3 in File S1). Data from comparative
meta-analysis performed for specific KCNK genes in cancer sub-
types in which a sufficient number of microarray studies (n$5)
examining these genes were available are presented in Tables 2, 3,
4, 5, 6 and was performed using all datasets in which the gene of
interest was examined and not just those which ranked above
threshold values. Meta-analysis provided the median gene rank
and median p-value, thus enabling comparison across different
microarray studies. If the median ranked analysis had a significant
p-value it indicated that the expression trend for that gene was
likely to be altered in that cancer subtype. If less than 5
independent studies for any of the genes in a particular cancer
subtype were not available on Oncomine, meta-analysis of data
which reached threshold was not performed but instead was
collated and presented in Table S3 in File S1.
Figure 1. Expression of KCNK genes across different cancers. Expression of KCNK genes (KCNK1–18) in 20 cancers compared to normal tissue
controls. Shown is the gene and protein names for each channel. A) overexpression of KCNK genes. B) underexpression of KCNK genes. Cancer types
are organised by their tissue of origin, the degree of colour correlates to the gene rank percentile of the highest ranking analyses. Search criteria were
for mRNA datasets and cancer vs. normal analysis only, with threshold values of p-value,0.05, fold change .2 and gene rank percentile ,10%.
doi:10.1371/journal.pone.0074589.g001
K
2P
Channel Expression in Cancer
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Two-pore domain weak inward rectifying K
+
(TWIK)
channel family
TWIK channels include KCNK1 (K
2P
1.1, TWIK1), KCNK6
(K
2P
6.1, TWIK2) and KCNK7 (K
2P
7.1). None of these channels
have previously been implicated in playing a role in cancer, but
analysis presented here reveals a significant overexpression of
KCNK1 in the majority of cancers analysed (12 out of 20 cancer
tissue types show overexpression with KCNK1 ranked in the top
10% of most altered genes) while 6 cancer tissue types showed
KCNK1 underexpression when compared to normal tissue
(Figure 1). KCNK6 was found to be among the top 1% of genes
overexpressed in breast cancer and top 1% of genes under-
expressed in colorectal cancer. While KCNK7 failed to show
overexpression in any of the cancer types examined it showed
significant underexpression in a range of cancers and was in the
top 1% of underexpressed genes in both melanoma and cervical
cancers (Figure 1).
Cancer subtypes in which KCNK1 showed above threshold
changes in expression are presented in Table 2 (if sufficient studies
were available for meta-analysis (n$5)) or Table S3 in File S1 (if
insufficient number of studies were available for meta-analysis
(n#4)). All cancer sub-types with KCNK1 overexpression eligible
for meta-analysis were found to show significant levels of
overexpression (median p-value#0.05; Table 2). Lung adenocar-
cinomas had the most significant increase in expression compared
Table 2. TWIK family members expression in cancer.
Gene Cancer Subtype Above threshold analyses Median values
p-value Fold change % Ref p-value Gene rank n
KCNK1 Brain Glioblastoma Q1.72E-24 29.574 2 [9] 5.14E-06 560.5 8
Q1.80E-14 220.541 3 [10]
Q1.07E-08 28.483 3 [3]
Q1.03E-05 213.309 4 [6]
q5.89E-04 3.178 6 [5]
Breast Ductal q5.23E-04 2.515 5 [16] 0.002 2547 12
q7.18E-04 3.965 5 [12]
q1.00E-03 2.405 5 [15]
q4.00E-03 2.661 9 [12]
q1.10E-02 2.4 9 [13]
Lobular q2.20E-02 2.177 4 [13] 0.031 3848 5
Cervical Squamous Cell q9.70E-13 2.949 1 [20] 0.043 3326 5
Leukaemia Acute Lymphocytic q4.00E-03 2.173 5 [42] 9.04E-07 4799 7
Lung Adenocarcinoma q3.59E-07 3.984 2 [52] 8.51E-13 511 7
q5.38E-07 2.141 3 [46]
q2.35E-05 4.641 1 [47]
q6.21E-05 2.137 8 [51]
Squamous cell q5.98E-08 2.138 9 [49] 0.002 852 6
q2.61E-06 7.79 2 [47]
Pancreas Adenocarcinoma q9.83E-10 3.526 5 [71] 0.008 787.5 8
q2.61E-04 6.584 3 [72]
q1.41E-04 6.62 5 [73]
q1.21E-08 4.613 1 [74]
q2.00E-03 2.685 9 [75]
KCNK6 Breast Ductal q2.77E-19 2.161 9 [17] 0.076 5236 10
q1.00E-03 2.765 1 [14]
Colorectal Adenocarcinoma Q1.77E-18 22.071 4 [26] 0.028 4860 11
Q2.38E-15 22.11 7 [26]
Q9.37E-15 22.136 1 [26]
KCNK7 Cervical Squamous cell Q5.62E-10 26.76 1 [21] 7.99E-04 519 5
Q1.86E-08 23.055 1 [22]
Q7.99E-04 23.315 5 [22]
Gastrointestinal Adenocarcinoma Q1.60E-02 22.336 10 [29] 0.446 9583 5
The above threshold data for TWIK family members; KCNK1, KCNK6 and KCNK7 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-
value, fold change and gene rank percentile (%) for data which scored above threshold values (p-value,0.05, fold change .2 and gene rank percentile ,10%) are
shown. Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value.
Overexpression qand underexpression Qare indicated.
doi:10.1371/journal.pone.0074589.t002
K
2P
Channel Expression in Cancer
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to normal tissue, with a 3.2260.64 mean fold increase from the 4
studies which reached threshold for inclusion and a median p-
value of 8.51E-13 (n = 7; Table 2). While, pancreatic adenocar-
cinomas showed the highest mean (6SEM) fold increase
(4.8060.79) in KCNK1 transcript compared to the normal
controls in the 5 studies above threshold criteria.
Brain cancers of glial cell origin (astrocytoma, glioblastoma,
oligodendrioglioma), medulloblastoma and melanomas all showed
significant down regulation of KCNK1 with respect to normal
control tissues (Table S3 in File S1). All but glioblastoma had
insufficiently high number of independent analyses to enable
inclusion in comparative meta-analysis (Table S3 in File S1), while
in glioblastoma 4 above threshold analyses showed underexpres-
sion ranging from 8 to 20 fold decreases in KCNK1 transcript
expression whereas one study showed a 3 fold increase of KCNK1
mRNA (Table 2). Comparative meta-analysis of all 8 studies in
which KCNK1 transcript expression was examined revealed an
overall significant (p = 5.14E-6) decreased expression of KCNK1
in glioblastoma (Table 2). KCNK1 is not the only gene to show
apparently conflicting expression profiles but this may be due to
the broad groupings in each of the cancer types. Significantly this
is also observed for KCNK10 in brain glioblastoma (Table 3).
While KCNK6 shows overexpression in both ductal (average
fold change 2.46; n = 2) and invasive (fold change 3.57 (n = 1))
breast cancer, overall, KCNK6 and KCNK7 show more
transcript underexpression (Table 2). Though, meta-analysis of
KCNK6 expression in ductal breast cancer found the increased
expression not to reach significance (p = 0.076; n = 10). Both
KCNK6 and KCNK7 show underexpression in melanoma and
oesophageal adenocarcinomas. KCNK6 showed significant de-
creased expression in colorectal adenocarcinoma (median p-
value = 0.028; n = 11) with a mean (6SEM) fold decreased
expression of 2.1160.02 in the 3 above threshold analyses for
underexpression. KCNK7 underexpressed in Barrett’s oesophagus
when compared to normal tissue controls but insufficient numbers
of studies were available to enable further analysis (Table S3 in
File S1). KCNK7 showed significant down-regulation in cervical
squamous cell carcinoma (median p-value of 7.99E-04; n = 5) with
a mean (6SEM) fold decreased expression of 4.3761.19. A
decreased expression of KCNK7 observed in gastrointestinal
adenocarcinomas failed to show significance following meta-
analysis (median p-value 0.446, n = 5) and achieved a median gene
rank of 9583 out of circa 14000 genes suggesting that alterations in
KCNK7 expression are less important in gastrointestinal adeno-
carcinomas.
TWIK-related K
+
(TREK) channel family
The TREK family has 3 family members KCNK2 (K
2P
2.1,
TREK1), KCNK4 (K
2P
4.1, TRAAK) and KCNK10 (K
2P
10.1,
TREK2). KCNK4 failed to show altered expression above the set
thresholds in the 20 cancers examined and therefore was not
further analysed.
KCNK2 was among the top 5% of genes over expressed in lung
cancers and under expressed in breast, gastrointestinal and head
and neck cancers (Figure 1). KCNK10 was among the top 1% of
genes underexpressed (compared to normal tissue controls) in
colorectal and kidney cancers while in breast and brain cancers
KCNK10 was among the top 5% of genes underexpressed
(Figure 1A & B). As seen with KCNK1 in glioblastoma, two of the
above threshold analyses show decreased KCNK10 expression
(compared to normal tissue controls) ranging from 2.9 to 4.8 fold
decreases, while a third analysis shows a 2.5 fold increase in
KCNK10 expression. Meta-analysis including all studies in which
KCNK10 expression was examined in glioblastoma cancer
revealed a significant decreased expression (median p-va-
lue = 5.03E-05; n = 5) but while clear changes in KCNK10
expression levels are observed in glioblastoma further studies
and analysis are required to determine the nature of these
alterations. KCNK10 was also ranked in the top 10% of over-
expressed genes in acute myeloid leukemia (Figure 1A & Table S3
in File S1; n = 4) but insufficient studies were available to enable
robust meta-analysis to be performed to determine the significance
Table 3. TREK family members expression in cancer.
Gene Cancer Subtype Above threshold analyses Median value
p-value Fold change % Ref p-value Gene rank n
KCNK2 Breast Invasive Q5.70E-05 22.23 4 [19] 0.349 8095 11
Lung Squamous cell q2.98E-04 2.111 5 [48] 0.696 6505 5
KCNK10 Brain Glioblastoma Q1.81E-17 24.843 5 [9] 5.03E-05 908 5
Q1.56E-10 22.974 6 [10]
q8.63E-04 2.547 7 [5]
Breast Ductal Q1.00E-03 22.294 2 [18] 0.15 6686.5 10
Q3.85E-04 23.523 2 [14]
Colorectal Adenocarcinoma Q1.74E-25 27.227 1 [26] 8.12E-07 372.5 14
Q3.19E-22 27.914 2 [26]
Q2.85E-18 26.275 1 [26]
Q2.07E-14 24.83 2 [26]
Q1.11E-07 26.275 2 [26]
Q3.42E-07 22.503 3 [26]
The above threshold data for TREK family members; KCNK2 and KCNK10 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-value,
fold change and gene rank percentile (%) for data which scored above threshold values (p-value,0.05, fold change .2 and gene rank percentile ,10%) are shown.
Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value.
Overexpression qand underexpression Qare indicated.
doi:10.1371/journal.pone.0074589.t003
K
2P
Channel Expression in Cancer
PLOS ONE | www.plosone.org 6 October 2013 | Volume 8 | Issue 10 | e74589
of this change. KCNK10 shows decreased expression in breast
ductal and lobular carcinomas and colorectal adenoma, adeno-
carcinoma and carcinoma as well as kidney clear cell carcinoma
(Table 3 & Table S3 in File S1). Only breast ductal carcinoma and
colorectal adenocarcinoma had sufficient number of studies to
enable meta-analysis (Table 3). This analysis revealed the changes
in breast ductal carcinoma not to be significant (median p-
value = 0.15; n = 5) while colorectal adenocarcinoma showed
significant decreased expression of KCNK10 (median p-va-
lue = 8.12E-07; n = 14)
KCNK2 showed decreased expression in invasive breast cancer,
gastrointestinal adenocarcinoma and head and neck squamous cell
carcinoma but these studies either failed to be included in meta-
analysis due to low study numbers or failed to show significance
following meta-analysis (Table 3 & Table S3 in File S1).
These data while limited by the sample size provide sufficient
evidence to warrant further investigation into the role of KCNK10
in both glioblastoma and colorectal adenocarcinoma.
TWIK-related acid sensitive K
+
(TASK) channel family
The TASK family has three members KCNK3 (K
2P
3.1,
TASK1), KCNK9 (K
2P
9.1, TASK3) and KCNK15 (K
2P
15.1,
TASK5).
Table 4. TASK family members expression in cancer.
Gene Cancer Subtype Above threshold analyses Median value
p-value Fold change % Ref p-value Gene rank n
KCNK3 Brain Glioblastoma Q6.20E-08 25.468 10 [10] 0.007 1486 7
Q2.61E-05 24.471 3 [10]
Breast Invasive q4.41E-17 2.782 4 [11] 0.005 8863 13
q1.50E-02 2.958 6 [14]
Q1.00E-03 22.375 7 [17]
Colorectal Adenoma Q2.37E-04 22.493 10 [24] 2.37E-04 1814 5
Q2.00E-03 24.175 5 [24]
Gastrointestinal Adenocarcinoma q2.85E-04 3.567 6 [28] 1 10604 6
Kidney Clear cell q1.53E-14 8.407 1 [36] 1.14E-04 990 6
q2.57E-07 6.014 5 [36]
q4.01E-05 4.541 7 [38]
q1.89E-04 6.344 6 [41]
Leukemia Acute lymphocytic q1.30E-02 2.177 9 [42] 0.994 8503 7
Lung Adenocarcinoma Q6.55E-34 24.136 1 [50] 4.33E-11 146.5 6
Q8.44E-20 26.89 1 [49]
Q8.67E-11 27.375 2 [52]
Q4.11E-10 22.367 1 [51]
Q2.54E-06 27.399 3 [47]
Q1.08E-04 23.803 4 [48]
Squamous cell Q5.90E-20 212.756 2 [49] 5.90E-20 343 5
Q3.86E-06 28.471 3 [47]
Q1.58E-05 24.28 3 [48]
Q2.00E-03 22.422 7 [53]
Pancreas Adenocarcinoma Q7.34E-06 26.459 1 [74] 2.46E-07 2997 7
Q4.72E-05 25.03 1 [72]
Q1.19E-04 22.191 3 [75]
Prostate Carcinoma Q2.72E-08 22.034 3 [77] 0.029 1515 13
Q1.02E-04 22.638 2 [79]
Q8.94E-04 23.106 4 [76]
KCNK9 Breast Invasive q1.16E-12 3.95 9 [11] 0.459 10188.5 14
KCNK15 Breast Ductal q1.00E-03 5.046 6 [12] 0.008 1578 6
q8.00E-03 2.283 9 [12]
q4.10E-02 8.774 8 [14]
Gastrointestinal Adenocarcinoma Q3.00E-03 22.189 5 [29] 0.043 2990 5
The above threshold data for TASK family members; KCNK3, KCNK9 and KCNK15 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-
value, fold change and gene rank percentile (%) for data which scored above threshold values (p-value,0.05, fold change .2 and gene rank percentile ,10%) are
shown. Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value.
Overexpression qand underexpression Qare indicated.
doi:10.1371/journal.pone.0074589.t004
K
2P
Channel Expression in Cancer
PLOS ONE | www.plosone.org 7 October 2013 | Volume 8 | Issue 10 | e74589
KCNK3 showed altered expression in the majority of cancers
examined (13 out of 20) and was in the top 1% of up-regulated
genes in kidney cancer and top 5% of up-regulated genes in breast,
leukaemia and lymphoma (Figure 1A). KCNK3 was in the top 1%
of under-expressed genes in sarcoma, breast, lung and pancreatic
cancers. KCNK3 was also in the top 5% of under-expressed genes
in cancers of the CNS, bladder, colorectal and prostate (Figure 1B).
Detailed meta-analysis of cancer subtypes with decreased KCNK3
expression revealed underexpression to be significant in pancreatic
adenocarcinoma (median p-value = 2.46E-07; n = 7), lung adeno-
carcinoma (median p-value = 4.33E-11; n = 6), colorectal adeno-
ma (median p-value = 2.37E-04; n = 5) and glioblastoma (median
p-value = 0.007; n = 7; Table 4). Lung squamous cell carcinoma
showed both the highest level of significance following meta-
analysis of 5 studies in which KCNK3 gene expression was
examined (median p-value = 5.90E-20) and highest mean fold
decrease in KCNK3 expression from the 4 studies which reached
threshold (6.9862.30; Table 4).
Analysis of KCNK3 transcript expression in specific cancers
within the broad cancer types shows significant increase in
KCNK3 expression in invasive breast (median p-value = 0.005)
and clear cell kidney (median p-value = 1.14E-04) cancers with a
4.5 to 8.4 fold increase in expression in clear cell kidney
carcinomas when compared to normal tissue controls (Table 4).
While K
2P
9.1 has previously been identified in breast, colon and
melanoma cancers [78,82,83], KCNK9 only showed an above
threshold analysis for invasive breast carcinomas (p-value = 1.16E-
12; Table 4). When comparative meta-analysis was performed
with 14 analyses examining KCNK9 in invasive breast carcino-
mas, the changes were found not to be significant (median p-
value = 0.459).
KCNK15 shows significant overexpression, by comparative
analysis, in ductal breast carcinomas (median p-value = 0.008;
5.3761.88 mean fold increase in 3 above threshold analyses) and
underexpression in gastrointestinal adenocarcinomas (median p-
value = 0.043; Table 4).
TWIK-related alkaline pH activated K
+
(TALK) channel
family
The TALK family has three family members KCNK5 (K
2P
5.1,
TASK2), KCNK16 (K
2P
16.1, TALK1) and KCNK17 (K
2P
17.1,
TALK2). KCNK16 failed to show altered expression above the set
thresholds in the 20 carcinomas examined initially and therefore
was not further analysed.
KCNK5 showed altered expression in 50% of cancers
examined. It was in the top 1% of up-regulated genes in
esophageal cancers and top 5% of up-regulated genes in breast
and lung cancers (Figure 1A). Decreased expression of KCNK5
was observed in a wider range of cancer subtypes with KCNK5 in
the top 1% of under-expressed genes in melanoma and top 5% of
under-expressed genes in breast, colorectal, kidney, leukaemia,
liver cancers and sarcoma (Figure 1B). Although not all cancer
subtypes which demonstrated changes in expression of KCNK5
had sufficient number of studies for comparative analysis (Table
S3 in File S1), meta-analysis of colorectal adenocarcinoma studies
showed a significant decrease in KCNK5 expression (median p-
Table 5. TALK family members expression in cancer.
Gene Cancer Subtype Above threshold analyses Median value
p-value Fold change % Ref p-value Gene rankn
KCNK5 Breast Ductal q2.14E-04 2.977 3 [12] 0.233 4729 9
Q7.70E-04 23.629 4 [12]
Q2.00E-03 22.498 2 [18]
Q1.00E-03 23.856 6 [12]
Colorectal Adenocarcinoma Q2.42E-12 23.18 3 [26] 2.35E-07 1052 11
Q1.95E-11 22.498 5 [26]
Q7.86E-08 23.199 2 [26]
KCNK17 Breast Invasive q2.20E-02 3.265 8 [14] 0.752 14529 12
The above threshold data for TALK family members; KCNK5 and KCNK17 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-value,
fold change and gene rank percentile (%) for data which scored above threshold values (p-value,0.05, fold change .2 and gene rank percentile ,10%) are shown.
Comparative meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value.
Overexpression qand underexpression Qare indicated.
doi:10.1371/journal.pone.0074589.t005
Table 6. THIK family member, KCNK13 expression in cancer.
Gene Cancer Subtype Above threshold analyses Median value
p-value Fold change % Ref p-value Gene rank n
KCNK13 Breast Invasive q3.35E-12 3.193 10 [11] 0.399 10349 11
q4.99E-08 2.05 10 [17]
The above threshold data for THIK family member; KCNK13 is shown. Data is divided into each cancer type and subtypes within that cancer. The p-value, fold change
and gene rank percentile (%) for data which scored above threshold values (p-value,0.05, fold change .2 and gene rank percentile ,10%) are shown. Comparative
meta-analysis was performed using all available analyses for a given cancer subtype which provides median gene rank and median p-value. Overexpression qand
underexpression Qare indicated.
doi:10.1371/journal.pone.0074589.t006
K
2P
Channel Expression in Cancer
PLOS ONE | www.plosone.org 8 October 2013 | Volume 8 | Issue 10 | e74589
value = 2.35E-07; n = 11; Table 5) with a mean fold decrease of
2.9660.23 (n = 4). Further studies are required to determine if the
down-regulation of KCNK5 observed in other cancer subtypes are
also significant.
A single study reached the threshold criteria and showed a 3.26
fold increase in KCNK17 expression in invasive breast carcinomas
(Table 5). However when comparative meta-analysis was per-
formed with all analyses examining KCNK17 in invasive breast
carcinomas (n = 12) it was found not to be significant (median p-
value = 0.752) suggesting the study which reached threshold may
not be representative of KCNK17 expression in breast cancer.
Two pore domain halothane inhibited K
+
(THIK) channel
family
The THIK family has two family members KCNK12 (K
2P
12.1,
THIK1) and KCNK13 (K
2P
13.1, THIK2).
KCNK12 showed altered expression compared to normal tissue
controls in 7 of the 20 cancer types examined with both
overexpression and underexpression observed (Figure 1 & Table
S3 in File S1). Above threshold reductions in KCNK12 expression
were observed in astrocytoma and glioblastoma, while increased
expression was seen in acute lymphocytic leukaemia and lung
adenocarcinoma but insufficient sample sizes for any of these
cancer subtypes prevented any comparative meta-analysis of
KCNK12 to be performed. KCNK13 showed two above
threshold analysis for invasive breast carcinomas with 2.6260.57
mean (6SEM) fold increase in KCNK13 expression. However
when comparative analysis was performed with 11 analyses
examining KCNK13 in invasive breast carcinomas, altered
expression of KCNK13 failed to reach significance (median p-
value = 0.399; Table 6).
Potential role for K
2P
channels in cancer therapy
This study provides a comprehensive overview of the current
data available on KCNK gene family expression in cancer and
clearly demonstrates altered expression of these genes is observed
in the majority of cancer types examined. In all of the 20 cancers
examined with the exception of ovarian cancer KCNK genes were
found in the top 10% of altered genes and were in the top 1% in
13 of these cancers. In several instances, specific cancer subtypes
show changes in a number of KCNK genes. Specifically brain
glioblastoma showed significant down regulation of KCNK1,
KCNK3 and KCNK10; while KCNK12 also showed decreased
expression but insufficient studies were available to enable
comparative analysis. Likewise, breast ductal cancer showed
significant increased expression of KCNK1, KCNK6 and
KCNK15. Noteworthy is the observation that in some cancer
subtypes overexpression of one KCNK gene occurs alongside
underexpression of another, this is observed in lung adenocarci-
noma, lung squamous and pancreatic adenocarcinomas, where in
all three of these cancer subtypes KCNK1 shows significant over-
expression while KCNK3 is significantly under-expressed. As
specific K
2P
family members show altered sensitivities to different
modulators such as intracellular and extracellular pH (TWIK,
TREK, TASK, TALK), hypoxia and reactive oxygen species
(TASK, TALK, THIK) and glucose concentration (TASK),
changing the relative expression of different K
2P
channels may
impact the response of cells to environmental cues [81–83,91–96].
Moreover, either increased or decreased expression of these
channels has the potential to induce membrane hyperpolarisation
or depolarisation respectively. As noted previously, alterations to
membrane potential is recognised to drive changes in cell
proliferation, apoptosis and migration [14–18,21]. As K
2P
channels are active over physiological membrane potential ranges,
this means these channels are ideally positioned to directly impact
cellular membrane potential at rest. This, together with their acute
sensitivity to the internal and external environment of the cell
which is known to change in the cancer microenvironment means
that altered expression of these channels may provide cancer cells
with a survival advantage.
Understanding the molecular and pharmacological regulation
of these channels together with a detailed knowledge of the
expression of these channels in cancer will enable these important
membrane proteins to be considered as potential therapeutic
targets in cancer treatment.
Supporting Information
File S1 Contains Tables S1, S2, and S3. Oncomine
datasets for all above threshold analyses used in this
study. Datasets are referenced in text from 1–80 and indicated is
the Oncomine nomenclature for a study, the original publication
reference and sample descriptions. (Information from www.
oncomine.org , Compendia Bioscience, Ann Arbor, MI).
(DOCX)
Acknowledgments
We are grateful to the contributors of data to Oncomine and those who
have made their data publicly available.
Author Contributions
Conceived and designed the experiments: IO SW AB. Performed the
experiments: SW. Analyzed the data: SW IO. Contributed reagents/
materials/analysis tools: AB. Wrote the paper: IO SW.
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... In 2013, a systemic screening of the mRNA expression of fifteen K 2P channels was conducted in 20 types of cancer by using Oncomine, an online cancer microarray database, together with a meta-analysis. Despite heterogeneous expression of K 2P channels among different cancers, overexpression of KCNK1 and KCNK15 was observed in most cancers (bladder, breast, cervical, lung, pancreatic, head and neck cancer, and leukemia), whereas KCNK3 and KCNK10 were downregulated in breast, lung, pancreatic cancer, and sarcoma [13,28]. ...
... Leukemia. Overexpression of KCNK3, KCNK10, and KCNK12 and downregulation of KCNK6 was found in patients with leukemia, resistant hematopoietic cancers, and acute myeloid leukemia (AML) [13,28]. KCNK15 was linked with acute lymphoid leukemia by altering DNA methylation in peripheral blood mononuclear cells (PBMCs) from patients [33]. ...
... Melanoma. TASK3 intracellular positivity was found in human melanoma tissue and three primary and metastatic human melanoma cell lines (WM35, HT199, and HT168-M1) [35], while KCNK5 was downregulated in melanoma patient samples [13]. KCNK7 was suggested as a disease biomarker and molecular target in melanoma patient specimens from a study concerned with the in silico identification and experimental validation [36]. ...
Article
Full-text available
The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.
... These membrane proteins are expressed in the central and peripheral nervous systems (playing a critical role in regulating membrane potential and input resistance in neurons) [1], astrocytes (mediating fast and slow glutamate release) [2], the cardiovascular system (upregulation of atrial K 2P currents was described in patients suffering from atrial fibrillation) [3], and the cochlea (likely regulating endolymphatic K + homeostasis in the inner ear) [4]. Their expression is up-and downregulated in different cancer cells [5], suggesting a wide spectrum of functions to these channels [6], including, but not limited to cell signaling, behavior [1], normal hearing [4], breathing control [7], anesthesia [8], and tumorigenesis [5]. These aspects provide unique attributes to this superfamily of proteins as potential druggable targets for drug discovery [6]. ...
... These membrane proteins are expressed in the central and peripheral nervous systems (playing a critical role in regulating membrane potential and input resistance in neurons) [1], astrocytes (mediating fast and slow glutamate release) [2], the cardiovascular system (upregulation of atrial K 2P currents was described in patients suffering from atrial fibrillation) [3], and the cochlea (likely regulating endolymphatic K + homeostasis in the inner ear) [4]. Their expression is up-and downregulated in different cancer cells [5], suggesting a wide spectrum of functions to these channels [6], including, but not limited to cell signaling, behavior [1], normal hearing [4], breathing control [7], anesthesia [8], and tumorigenesis [5]. These aspects provide unique attributes to this superfamily of proteins as potential druggable targets for drug discovery [6]. ...
Article
Full-text available
TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader—Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC50 ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.
... Potassium channel subfamily K member 6 (KCNK6) is a background potassium channel belonging to the double-pore domain potassium channel family, that facilitates the leakage of potassium ions out of cells primarily by regulating the resting membrane potential and life process of cells. Although KCNK6 is reportedly overexpressed in breast cancer cells (Williams et al., 2013), its role in malignant progression of tumors, has not been reported. Due to various unique characteristics of potassium channels, their altered expression may be useful for diagnosis and treatment. ...
... Many studies have shown that potassium channels, including KCNN4 (Steudel et al., 2017), KCNA1 (Lallet-Daher et al., 2013), Kv11.1 (Breuer et al., 2019), KCNK9 (Mu et al., 2003;Sun et al., 2016), KCNE1 (Becchetti et al., 2017), and GIRK1 (Stringer et al., 2001) are involved in the regulation of malignant breast cancer transformation. Although it has been reported that KCNK6 expression is increased in breast cancer (Williams et al., 2013) and thyroid carcinoma (Lin et al., 2020), its function had not been previously reported. Therefore, our study revealed, for the first time, that altered KCNK6 expression in breast cancer cell lines results in significant changes in cell adhesion and hardness, leading us to postulate that its expression will also affect the flow of potassium ions as well as the liquid flow, thereby directly impacting the cell hardness and adhesion. ...
Article
Full-text available
Breast cancer is the most common malignant tumor in women, and its incidence is increasing each year. To effectively treat breast cancer, it is important to identify genes involved in its occurrence and development and to exploit them as potential drug therapy targets. Here, we found that potassium channel subfamily K member 6 (KCNK6) is significantly overexpressed in breast cancer, however, its function in tumors has not been reported. We further verified that KCNK6 expression is upregulated in breast cancer biopsies. Moreover, overexpressed KCNK6 was found to enhance the proliferation, invasion, and migration ability of breast cancer cells. These effects may occur by weakening cell adhesion and reducing cell hardness, thus affecting the malignant phenotype of breast cancer cells. Our study confirmed, for the first time, that increased KCNK6 expression in breast cancer cells may promote their proliferation, invasion, and migration. Moreover, considering that ion channels serve as therapeutic targets for many small molecular drugs in clinical treatment, targeting KCNK6 may represent a novel strategy for breast cancer therapies. Hence, the results of this study provide a theoretical basis for KCNK6 to become a potential molecular target for breast cancer treatment in the future.
... K 2P channels are involved in ion homeostasis, hormone secretion, cell development, and excitability. Therefore, these channels play a role in many physiological and pathological mechanism such as vascular and pulmonary hypertension, cardiac arrhythmia, nociception, neuroprotection, taste and temperature sensing, anesthesia, apoptosis, carcinogenesis, and depression (Patel and Honore, 2001;Bayliss and Barrett, 2008;Enyedi and Czirják, 2010;Lloyd et al., 2011;Williams et al., 2013;Feliciangeli et al., 2015;Kim and Kang, 2015). ...
... Besides the heart, the TASK-1 channel is expressed in the liver, placenta, prostate, kidney, lung, pancreas, ovary, small intestine, and brain (Lesage and Lazdunski, 2000;Williams et al., 2013). Therefore, it is involved in a variety of physiological and pathophysiological processes. ...
Article
Full-text available
Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.
... The TWIK-1 was detected as an upregulated channel in pancreatic ductal adenocarcinoma (PDAC) compared to normal tissue. 115 Recently, TWIK-2 (K2P6, encoded by KCNK6 gene) was reported as a significantly overexpressed channel in breast cancer. 120 Moreover, the overexpression of TWIK-2 increases the capacity of proliferation, invasion, and migration of breast cancer cells. ...
Article
Full-text available
Potassium (K+) channels are highly regulated membrane proteins that control the potassium ion flux and respond to different cellular stimuli. These ion channels are grouped into three major families, Kv (voltage-gated K+ channel), Kir (inwardly rectifying K+ channel) and K2P (two-pore K+ channels), according to the structure, to mediate the K+ currents. In cancer, alterations in K+ channel function can promote the acquisition of the so-called hallmarks of cancer - cell proliferation, resistance to apoptosis, metabolic changes, angiogenesis, and migratory capabilities - emerging as targets for the development of new therapeutic drugs. In this review, we focus our attention on the different K+ channels associated with the most relevant and prevalent cancer types. We summarize our knowledge about the potassium channels structure and function, their cancer dysregulated expression and discuss the K+ channels modulator and the strategies for designing new drugs.
... Members of the subfamily, the TWIK-related alkaline pH activated potassium channels including TASK-2, TALK-1, and TALK-2, are stimulated by an extracellular alkalinization (Dookeran and Auer 2017;Pei et al. 2003;Patel and Lazdunski 2004). These channels are of interest as their genes have been found to be either altered or upregulated in BC tissue, and in some cell types are found to be required for apoptosis (Dookeran and Auer 2017;Pei et al. 2003;Patel and Lazdunski 2004;Williams et al. 2013). These channels are inhibited by an extracellular acidification, which may contribute to cancer cells avoiding apoptosis through these channels (Andersen et al. 2014). ...
... All of these channels play a critical role in the control of cell excitability as well as in cell volume regulation, proliferation, migration and apoptosis. Thus, altered expression of K + channel has been widely associated with a growing number of diseases, including cancer [12,14,[19][20][21][22][23][24]. ...
Article
Full-text available
Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development.
... Five of these ten genes in the novel loci are involved in cardiovascular conditions and six in cancer processes. 77,[97][98][99][100][101][102][103][104][105][106][107][108] Three loci that were novel in GBMI, ANGPTL7, CCDC13, and LHPP, were attenuated to sub-genome wide significance level in GBMI-IGGC-GGLAD meta-analysis (p-values of 0.0043, 6.202e-08 and 2.506e-07, respectively, Suppl. Table S3, S7, S12). ...
Preprint
Full-text available
Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that, if untreated, ultimately leads to irreversible blindness. To date, the biological mechanisms causing POAG are still unclear. There is disparity in POAG prevalence, clinical presentations, and outcomes across ancestries. Here, we aim to identify unique genetics that underlies risk to POAG and evaluate the potential connection with vascular mechanisms. We performed POAG meta-analysis across 15 biobanks that are part of the Global Biobank Meta-analysis Initiative, with two previously published multi-ancestry analyses for a total of 1,478,037 individuals from six ancestries (46,325 cases and 1,431,712 controls). A total of 109 genome-wide significantly associated loci (p<5e-8) were identified, 18 of which were novel. Three of these novel loci are ancestry-specific, two African- specific and the third specific to northern Europeans. We also identified five sex-specific novel loci, four of which are African-specific and one European-specific. To explore biological implications underlying these variant-trait associations, we performed gene enrichment analysis, gene prioritization analysis and transcriptome-wide association studies (TWAS) implicating genes related to vascular-related functions, blood vessels, angiogenesis, and cancer. A fifth of TWAS-prioritized genes with vascular-related and/or cell senescence/proliferation functional roles or have been implicated in vascular or neoplastic diseases are primary ciliary related genes. We further performed extensive statistical validation analysis of genes in the SIX6 and well-known CDKN2B-AS1 loci, previously implicated in POAG, cardiovascular diseases, and cancers across multiple ancestries. We found evidence of significant interaction between SIX6 rs33912345 and causal variants in chr9p21.3, with concomitant effect on expression of a primary cilia gene CDKN2A and CDKN2B at the CDKN2B-AS1 locus. Phenome-wide association analysis of POAG genetic risk burden across five biobanks and genetic correlation analysis also show the shared biology between POAG and vascular and neoplastic traits. In summary, our findings suggest that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our findings further support the contribution of vascular and proliferation genes in POAG and suggest potential involvement of primary cilia in POAG pathogenesis.
... Several members of the Two Pore Domain family have been shown to be overexpressed in human tumors [62]. Quite recently, K2P6.1 (KCNK6) was shown to be expressed in breast cancer and to promote proliferation, migration and invasion [63]. ...
Chapter
Full-text available
Electrolyte disorders are a frequent finding in cancer patients. In the majority of cases the etiologies of such disorders are common to all cancer types (i.e. diuretic-induced hyponatremia or hypokalemia). Sometimes, electrolyte disorders are caused by paraneoplastic syndromes or are due to cancer therapy. Potassium is one of the most important electrolytes of the human body since it is involved in the regulation of muscle contraction, maintenance of the integrity of the skeleton, blood pressure and nerve transmission as well as in the normal function of cells. Potassium homeostasis is strictly regulated since the gap between the recommended daily dietary intake (120 mEq/day) and the levels stored in the extracellular fluid (around 70 mEq) is huge. Alterations of potassium homeostasis are frequent in cancer patients as well alterations in potassium channels, the transmembrane proteins that mediate potassium fluxes within the cells. The present chapter is focused on the clinical significance of potassium homeostasis and potassium channels in patients with solid tumors.
... Conversely, it has also been assumed that TASK-1 downregulation is the basis of heart failure [70]. Therefore, it seems that as in other pathologies and for other K2P channels [71], the dysregulation (up or down) of TASK is correlated with AF. ...
Article
Full-text available
Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later detected in cardiac tissue by RT-PCR, although the distribution of the different K2P subfamilies in the heart seems to depend on the species analyzed. In order to collect relevant information in this regard, we focus here on the TWIK, TASK and TREK cardiac channels, their putative roles in cardiac physiology and their implication in coronary pathologies. Most of the RNA expression data and electrophysiological recordings available to date support the presence of these different K2P sub-families in distinct cardiac cells. Likewise, we show how these channels may be involved in certain pathologies, such as atrial fibrillation, long QT syndrome and Brugada syndrome.
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