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The Warburg effect: 80 years on


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Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.
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The Warburg effect: 80 years on
Michelle Potter, Emma Newport and Karl J. Morten
Nuffield Department of Obstetrics and Gynaecology, The Women Centre, University of Oxford, John Radcliffe Hospital, Oxford, U.K.
Correspondence: Karl J. Morten (
Inuential research by Warburg and Cori in the 1920s ignited interest in how cancer cells
energy generation is different from that of normal cells. They observed high glucose con-
sumption and large amounts of lactate excretion from cancer cells compared with normal
cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer
cells were generating energy using glycolysis rather than mitochondrial oxidative
phosphorylation, and that the mitochondria were dysfunctional. Advances in research
techniques since then have shown the mitochondria in cancer cells to be functional
across a range of tumour types. However, different tumour populations have different
bioenergetic alterations in order to meet their high energy requirement; the Warburg
effect is not consistent across all cancer types. This review will discuss the metabolic
reprogramming of cancer, possible explanations for the high glucose consumption in
cancer cells observed by Warburg, and suggest key experimental practices we should
consider when studying the metabolism of cancer.
The Warburg effect
Despite decades of research and countless nancial investments, cancer continues to elude our
complete understanding and more importantly our therapies. Pivotal research in the 1920s by
Warburg and Cori demonstrated that cancer avidly consumes glucose and excretes lactate [1,2]. When
oxygen is present, normal cells use mitochondria to oxidise glucose, but in the absence of oxygen,
glucose is converted into lactate. Otto Warburg rst described in the 1920s that cancer cells utilised
higher levels of glucose in the presence of oxygen with an associated increase in lactate production.
The phenomenon of aerobic glycolysis, termed the Warburg effect, has been observed in a variety of
other tumour types, including colorectal cancer [3], breast [4], lung [5] and glioblastoma [6,7]. From
his observations, Warburg concluded that the mitochondria were dysfunctional [8,9]. The Warburg
effect has been conrmed in previous studies including those of DeBerardinis et al. [10], where cells
were incubated under oxygenated conditions in 10 mM C-13-labelled glucose. Cells were then per-
fused using 4 mM glucose prior to metabolomics analysis and even in the presence of oxygen, high
levels of glycolytic metabolites were observed supporting Warburgs hypothesis. In addition, Fantin
et al. [11] made the observation that inhibiting lactate dehydrogenase preventing the conversion of
pyruvate to lactate reduced tumourigenicity. These data were interpreted as tumourigenicity being
dependent on high levels of energy derived from glycolysis. Another study by Schulz et al. [12]
showed that when mitochondrial oxidative phosphorylation is up-regulated by overexpression of fra-
taxin, malignant growth and tumourigenic capacity are decreased. The authors suggest that rather
than an increase in glycolysis being the main cause of malignant tumour growth, it is the efciency of
mitochondrial energy conversion that is the key metabolic factor.
Over the past couple of decades, advances in technology have allowed mitochondrial function to be
studied in a far greater detail, and it is now realised that cancer cells have active and functional mito-
chondria, contrary to Warburgs theory [13,14]. In the last decade, research has shown that different
tumour types (and indeed subpopulations within a tumour) have different bioenergetic alterations.
This was shown as early as 1967, when Weinhouse reported that slow-growing rat hepatoma cells
were oxidative, whereas the more proliferative hepatomas were glycolytic [15]. The Warburg effect is
not consistent across all tumours, and the phenomenon of aerobic glycolysis has now been challenged
by several groups with many cell lines reported as having mitochondrial function [1618]. In a
Version of Record published:
19 October 2016
Received: 1 April 2016
Revised: 29 June 2016
Accepted: 25 July 2016
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Biochemical Society Transactions (2016) 44 14991505
DOI: 10.1042/BST20160094
tumour, it is likely that a dynamic interplay exists between oxidative metabolism and glycolysis. Metabolic exi-
bility has now been observed in a range of cancers, including cervical, breast and pancreatic cancer (see ref.
[16] and reviewed in ref. [19]). In 2004, Zu and Guppy reported that adenosine triphosphate (ATP) derived
through glycolysis in various cancers and cell lines accounts for only 17% of the total ATP. In fact, the ATP
generated through glycolysis was highly dependent on the cell type and could be as low as 0.31% (brosar-
coma) or as high as 64% (hepatoma), with the remaining ATP being derived from mitochondrial oxidative
phosphorylation [20]. In addition to metabolic exibility linked to environmental conditions, there is also the
inuence of various cancer-associated mutations, many of which have an impact on metabolism. Mutations in
the mitochondrial tricarboxylic acid cycle and respiratory chain component succinate dehydrogenase, for
example, can cause phenochromocytoma and paraganglioma, where neuroendocrine tumours arise in the
adrenal medulla and paraganglia in the autonomic nervous system [21,22]. Mutations in isocitrate dehydrogen-
ase 1 are associated with adult cases of glioblastoma and appear to have a major role in the development of the
tumour by a gain-of-function effect [23,24]. Understanding how cancer cell environment and mutations affect
metabolism will be of fundamental importance in selecting appropriate metabolic drug combinations to impact
on patientscancer cell growth.
Cancer hallmarks and metabolic reprogramming
Cancer cells show complex, dynamic behaviour allowing survival even in the most unfavourable conditions of
substrate and oxygen stress. Advances in technology have helped in furthering our knowledge of the underlying
molecular processes underpinning cancer, but there are still many unanswered questions. In 2000, Hanahan
and Weinberg published a highly cited review article identifying six cancer hallmarks [25]. These included
uncontrolled proliferative signalling, resistance to apoptosis, initiating angiogenesis, acquiring replicative
immortality, activating invasion and metastasis and evading growth suppressors. Over the last decade, research
has increased our knowledge of cancer, and in 2011, Hanahan and Weinberg extended the list of cancer hall-
marks to include metabolic reprogramming/deregulated cellular energetics as an emerging hallmark and potential
cancer target [26]. Uncontrolled proliferation is one of the essential characteristics of cancer. It has been
proposed that reprogramming energy metabolism is essential to fuel and maintain such behaviour [26]. The
exact reasons behind the metabolic switch are not known, but likely reasons include: (i) sustaining high prolif-
erative rates in hypoxia [27] and (ii) evading apoptosis as a result of reduced mitochondrial function [28].
Increases in glycolysis have been linked to invasiveness, with changes in glycolysis identied in several studies
[29,30]. However, in all studies listed above, cancer cells were grown on cell culture media containing high
levels of glucose between 10 and 25 mM. This is considerably higher than plasma glucose, which lies between 4
and 6 mM. Levels in a rapidly dividing tumour with poor vasculature are considerably lower. The same is true
of studies investigating the role of hypoxia in down-regulating mitochondrial respiration and increasing glycoly-
sis, where 25 mM glucose is used in the culture media of key publications [3134]. The impact of high levels of
glucose on the above ndings is a key consideration for future studies, where it is crucial to test new drugs tar-
geting cancer cell metabolism under physiologically relevant conditions. Metformin, for example, a drug cur-
rently being investigated as an anticancer agent in a wide range of cancers [35], has recently been shown to be
more effective in enhancing chemotherapy sensitivity of oesophageal squamous cancer cells under reduced
glucose conditions [36]. Although its mode of action on cancer cells in vivo is not entirely clear, mitochondrial
studies suggest that metformin can directly impair complex I of the respiratory chain [37,38]. The effect
observed by Yu et al. is probably due to a greater reliance of the cancer cells on mitochondrial respiration for
energy production when cultured on reduced glucose conditions. Previous studies have shown that high levels
of glucose in the culture media can signicantly reduce levels of mitochondrial respiration, with reduced
glucose conditions showing much higher rates of mitochondrial respiration, as cells use other substrates for
cellular ATP production [39,40]. Similar results are shown in Figure 1, where the oxygen consumption rates
(OCRs; mitochondrial respiration) and extracellular acidication rates (ECAR; glycolysis) of a range of cancer
cell lines are compared under high (25 mM) and low (1 mM) glucose conditions. Under high glucose (25 mM)
conditions, cancer cell lines either show the Warburg effect (low OCR and high ECAR), high rates of OCR and
low ECAR or something in between high/moderate OCR with high/moderate ECAR. A nding highly relevant
to the situation in vivo is that when cultured under low glucose (1 mM) conditions, all cancer lines tested show
highmoderate OCR with very little ECAR (glycolysis).
1500 © 2016 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).
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DOI: 10.1042/BST20160094
Positron emission tomography imaging and the reverse
Warburg effect
Positron emission tomography (PET) imaging uses a radioisotope-labelled glucose tracer,
F-uorodeoxyglucose (
F-FDG), to identify areas of high glucose uptake/metabolism in the body.
F-FDG is
transported into cells by glucose transporters (GLUTs) and phosphorylated by hexokinase (HK) to
F-FDG-6-phosphate (
F-FDG-6-P). Once inside the cell,
F-FDG-6-P cannot be further metabolised
through the glycolytic pathway and due to its high polar nature becomes trapped. Tumours above a certain size
label strongly with this approach, and it is used to identify the presence of solid tumours and the effectiveness
of treatments. Other highly metabolically active tissues, such as the brain and heart, also label strongly. It is
believed that PET scans show an increased uptake of glucose in tumours due to overexpression of GLUTs
[4143]. Historically, increased glucose uptake has been associated with supporting the Warburg effect [20].
However, high glucose uptake does not automatically equate to increased glycolysis and reduced mitochondrial
metabolism. An increased PET signal could be due to a general increase in glucose oxidation with increased
glycolysis and mitochondrial respiration or a high demand for lipids derived from glucose. In addition, over-
expression of GLUTs cannot be assumed to correlate with increased metabolic ux. A high PET signal would
be obtained if glucose entered the cancer cell and was not metabolised. Many tumours are characterised by
Figure 1. Bioenergetic proles of cancer cell lines RD, RH30, U87MG, M059K, SF188, KNS42, UW479 and Res259.
OCR and ECAR are plotted to quantify mitochondrial respiration and to give an indication of glycolysis rates. OCR and ECAR
are expressed as changes in uorescence life time/h/75 000 cells (n= 3). Assays were set up in black 96-well plates with
pre-incubation in 1 mM and 25 mM glucose media carried out for 16 h. Oxygen and glycolysis sensing probes: MitoXpress xtra
and pH xtra from Luxcel Biosciences were used to determine OCR and ECAR (
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increased levels of GLUTs (particularly GLUT 1 and GLUT 3) and high expression of HK (I and II), which is
associated with the increases in
F-FDG signal compared with surrounding tissues as reviewed in ref. [44].
However, not all cancers are easily detected by PET imaging, including renal clear cell carcinoma, which is a
prototypical Warburg cancer [45]. Conversely, not all
F-FDG avid tissue is malignant; inammation can also
lead to a positive PET signal. Interestingly, Hodgkins lymphoma responds well to PET imaging [46]. This
tumour is less than 10% cancer cells, and the remaining cells are stromal/inammation cells [47].
Although PET imaging is undeniably an extremely useful and an important clinical technique, there can be
issues with the interpretation of the image. It is a common problem that the PET images can often overestimate
the actual size of the tumour. A possible reason for this is that the microenvironment of the tumour is glyco-
lytic in a phenomenon that has been called the reverse Warburg effect. First postulated by Pavlides et al. in
2009 [48], the reverse Warburg effect describes how oxidative stress in the cancer-associated broblasts (CAF)
induces mitophagy and autophagy. The hypothesis is that hydrogen peroxide secreted from the cancer cells
leads to oxidative stress in the CAF. The broblasts then undergo cellular catabolism, which results in a loss of
mitochondrial function and ultimately a switch from aerobic metabolism to glycolysis [49]. This glycolytic
switch results in increased lactate production by CAF, which is then exported into the extracellular space by
monocarboxylate transporter 4 (MCT4). The lactate is ultimately taken up by the cancer cells via MCT1 and
used to fuel oxidative metabolism [50,51]. In ref. [50], the authors demonstrate support for the reverse
Warburg effect by culturing human breast cancer cell lines with human broblasts. Both MCF-7 and
MDA-MB-231, when co-cultured with broblasts, show reduced mitochondrial function in broblasts with
increased activity in the cancer cell lines. As in the studies of the Warburg effect and the impact of hypoxia
described earlier, studies to date on the reverse Warburg effect use high concentrations of glucose 25 mM. If
glucose is rapidly removed from the media by the cancer cells, this would tend to drive the cancer cells to use
mitochondrial respiration (see Figure 1). Under high glucose conditions, this property of cancer cell lines will
be held back by glucose inhibition of mitochondrial respiration.
Lactate was discovered in the late 1700s and was traditionally thought of as a waste product of glycolysis. In
reality, lactate is an extremely efcient fuel and also an important signalling molecule [52,53]. It is constantly
turned around in our cells, regardless of oxygenation state. Lactate is a key metabolite in the body, capable
of replacing glucose as an energy source. Lactate is also capable of stabilising hypoxia-inducing factor and
increasing vascular endothelial growth factor expression [53]. The broblasttumour metabolic coupling
proposed to exist in the reverse Warburg effect is analogous to the metabolic symbiosis seen in the brain
(Figure 2). The brain is a metabolically demanding organ that gives high PET signals. Its avidity for glucose
was historically attributed to the neurons; however, it is the astrocytes that are glucose hungry and glycolytic.
The lactate secreted by the astrocytes then fuels the neurons, which use oxidative phosphorylation to generate
ATP [54]. The Warburg effect is not a universal feature of cancer, and similarly the reverse Warburg is not
universal in all tumours. Yoshida, in 2015, showed that tumours expressing high levels of MCT4 do no exhibit
the reverse Warburg effect [55]. The microenvironment of cancer is ever changing, and cancer cells can and
do vary in their metabolic phenotype even within the same tumour mass [56]. Although hard to generalise in
solid tumours with a hypoxic core, perhaps the Warburg effect most probably predominates with reduced
oxygen levels driving the cells to make the most of all available glucose. The more actively proliferating cells in
the periphery may perhaps use the lactate excreted in the hypoxic region and oxidise it [57], leading to a
symbiotic relationship between the hypoxic and aerobic cell populations. In vitro metabolism studies are
useful tools, but it only serves to hinder therapeutic translation when non-physiological glucose concentrations
up to and including 25 mM glucose are used instead of a physiological concentration of 5 mM (plasma) or
<5 mM (tissue).
In summary, we have sought here to revisit the Warburg effect and review its signicance in cancer based on
recent advances in our knowledge and understanding of the complex biology underlying this disease. It is
indisputable that certain features of cancer are indeed hallmarks that are essential for most types of cancer.
However, looking to the future, the role of aerobic glycolysis needs further elucidation, as it is not a consistent
feature in all cancers. Recent research has shown there to be a broad spectrum of bioenergetic phenotypes dis-
played by cancer both in vivo and in vitro, with many cancer types displaying a surprising degree of mitochondrial
activity. When investigating the role of aerobic glycolysis in vitro, it is pertinent to use physiologically relevant
concentrations of nutrients, in particular glucose. The excessive glucose often found in cell culture media can
decrease mitochondrial respiration, allowing aerobic glycolysis to predominate. Reducing the glucose in the
media to physiological levels will give a truer picture of the complex metabolic processes at work.
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Biochemical Society Transactions (2016) 44 14991505
DOI: 10.1042/BST20160094
F-FDG-6-phosphate; ATP, adenosine triphosphate; CAF,
cancer-associated broblasts; ECAR, extracellular acidication rate; GLUT, glucose transporter; HK, hexokinase;
MCT4, monocarboxylate transporter 4; OCR, oxygen consumption rate; PET, positron emission tomography.
Figure 2. The astrocyteneuron shuttle (A) and the reverse Warburg effect (B).
(A) Glutamate is released from activated synapses and taken up by astrocytes triggering an increase in glycolysis and lactate
production. The lactate can be oxidised by the neurons in response to their increased energy requirement to produce ATP.
(B) nIn the proposed reverse Warburg effect, hydrogen peroxide is secreted by cancer cells leading to oxidative stress in the
associated broblasts. The resulting loss of mitochondrial function acts as a switch from aerobic metabolism to glycolysis.
© 2016 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND). 1503
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DOI: 10.1042/BST20160094
Michelle Potter and Emma Newport were supported by Williams fund (
Competing Interests
The Authors declare that there are no competing interests associated with the manuscript.
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© 2016 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND). 1505
Biochemical Society Transactions (2016) 44 14991505
DOI: 10.1042/BST20160094
... Molecular epigenetics regulatory techniques can help plants to reproduce and survive in unexpected conditions by facilitating stable variations in the gene activity and fitting gene-expression pattern. Molecular polyploidization, or the growth in numbers of chromosomes sets, is ubiquitous in plants, expanding families of genes and promoting the functional capacity of duplicated genes, as well as those participating in the control of molecular epigenetics [4,5]. Understanding plant epigenetic regulatory mechanism has mostly come from the genetic screens, particularly in Arabidopsis thaliana, a part of mustard family which is very susceptible to the genetic analysis and it was the 1st species of plant to have sequenced genome. ...
... This glycosylation plays vital role in stability of proteins, cellular interactions, cell adhesion, signal transduction and in protein folding even. Therefore, a minor fault in the glycosylation may lead to serious metabolic, neoplastic and neurodegenerative disorders [1][2][3][4][5][6]. The classification of these glycosidic linkages is done on the basis of functional group on amino acids of protein part conjugated with the sugars. ...
... The effect of S-glycosylation compound on cytotoxicity of certain anti-tumor agents has been studied. In this case, it is investigated the cytotoxicity of thioglycoside derivatives of (1,3,4thiadiazolyl) thiaazaspiro [4,5] decane and thiazopyrimidine against three cell lines, i.e., HepG-2 (human liver hepatocellular carcinoma), HCT-116 (human colorectal carcinoma) and PC-3 (human prostate adenocarcinoma). The results revealed that that how these enhanced cytotoxic activities on test cell lines as compared to their equivalent aglycones [33][34][35][36]. ...
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Plants' reliance on molecular epigenetic control reflects their developmental, lifestyles, and the evolutionary histories. Plants grows by continually developing new parts from the self-sufficing stem cells population, termed as meristem, as opposed to mammals, whose tissues and organs formation is primarily determined during the embryo development. The interest in different medically active products has been developed to improve their pharmacokinetic and biological properties for utilizing glycosyl-conjugation. The conjugation of various drugs with various mono, di, or polysaccharides has boosted the therapeutic potentials of these drugs that is also manifested by a significant number of research papers. The current review article encapsulates extremely important and the up-to-date example of this conjugation, specially associated to enhancing antitumor activities of original glycoconjugates. The given examples along projected mechanisms of activities enhancement may guide to design, synthesize and evaluate new glycosyl conjugates for improved therapeutics.
... Normal and neoplastic PCs compete for space within the bone marrow [15], with neoplastic PCs able to overcome the micro-environment constraints to sustain their proliferation owing to their phenotypes [16]. This often results in an evolutionary advantage of malignant cells that relies on a metabolism that facilitates the uptake and incorporation of nutrients into the biomass [17][18][19][20][21]. In patients, myelomas emerge at different times relative to the malignancy of the disease that developed in a clinical classification of its different asymptomatic and symptomatic phases [22][23][24][25][26]. ...
... By estimating the parameters for the different phenotypes of normal and cancerous plasma cells, we show that, for increasing malignancy, neoplastic plasma cells set on more dissipative and stable states, reflecting a breakdown of regulation at the scale of the bone marrow which, according to the competition model, drives the onset of Multiple Myeloma. In our formulation, owing to a change in the growth rate, malignant cells are able to incorporate more nutrients into biomass by changing the boundary conditions for the system dynamics, namely the energy and resources inflow, in line with the biomedical phenomenology [17][18][19][20]. In the model, higher energy and resource inflows correspond to greater dissipations, reflecting open boundary conditions and a more dissipative metabolism for neoplastic PCs, an hypothesis which may be tested through the observation of heat shock proteins in neoplastic plasma cells [34] connected with measures of temperatures and heat flows [35]. ...
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Ecological interactions are fundamental at the cellular scale, addressing the possibility of a description of cellular systems that uses language and principles of ecology. In this work, we use a minimal ecological approach that encompasses growth, adaptation and survival of cell populations to model cell metabolisms and competition under energetic constraints. As a proof-of-concept, we apply this general formulation to study the dynamics of the onset of a specific blood cancer—called Multiple Myeloma. We show that a minimal model describing antagonist cell populations competing for limited resources, as regulated by microenvironmental factors and internal cellular structures, reproduces patterns of Multiple Myeloma evolution, due to the uncontrolled proliferation of cancerous plasma cells within the bone marrow. The model is characterized by a class of regime shifts to more dissipative states for selectively advantaged malignant plasma cells, reflecting a breakdown of self-regulation in the bone marrow. The transition times obtained from the simulations range from years to decades consistently with clinical observations of survival times of patients. This irreversible dynamical behavior represents a possible description of the incurable nature of myelomas based on the ecological interactions between plasma cells and the microenvironment, embedded in a larger complex system. The use of ATP equivalent energy units in defining stocks and flows is a key to constructing an ecological model which reproduces the onset of myelomas as transitions between states of a system which reflects the energetics of plasma cells. This work provides a basis to construct more complex models representing myelomas, which can be compared with model ecosystems.
... The aforementioned studies based on microRNA-targeted FOXO3a in hepatocellular carcinoma cells demonstrated a functionally opposite relationship between the microRNAs and the protein; however, a study closely related to metabolic reprogramming showed divergent findings. When the oxygen level is low, the efficiency of glycolysis in cancer cells is strengthened, supplying the energy needed for tumour growth, an outcome known as the Warburg effect (38). The P protein (HBp) encoded by the HBV virus interacts with FOXO3a to promote the activity of miR-30b-5p in HBV-positive hepatocellular carcinoma, and MINPP1 inhibits tumour cell proliferation. ...
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FOXO3a is a protein of the forkhead box family that inhibits tumour cell growth. One of the regulatory modes affecting the role of FOXO3a is microRNA targeting and degradation of its mRNA expression, and conversely, aberrant expression of FOXO3a as a transcription factor also influences microRNA levels. We summarized the results of the regulatory interactions of twenty-five microRNAs with FOXO3a in five types of malignant tumours and found that dual microRNAs synergize with FOXO3a to inhibit breast cancer cell growth including two groups; Three individual microRNAs collaborated with FOXO3a to restrain hepatocellular carcinoma progression; Twelve individual microRNAs antagonized FOXO3a to promote the development of a single tumour cell, respectively; and five microRNAs antagonized FOXO3a to contribute to the progression of more than two types of tumours. The above findings demonstrated the tumour suppressor effect of FOXO3a, but another result revealed that miR-485-5p and miR-498 inhibited the growth of hepatocellular carcinoma cells by antagonizing FOXO3a when acting in combination with other long-stranded non-coding RNAs, respectively, suggesting that FOXO3a at this moment plays the function of promoting the tumour progression. The PI3K/AKT, Snail, VEGF-NRP1, and Wnt/β-catenin signalling pathways perform crucial roles in the above process. It is anticipated that the above studies will assist in understanding the effects of FOXO3a-MicroRNA interactions in cancer genesis and development, and provide new perspectives in the treatment of malignant tumours.
... The penetration of such cations through the hydrophobic layer of lipid membranes is often the limiting stage of their accumulation in cells and mitochondria. In tumor cells characterized by hyperpolarized (in comparison with normal cells) mitochondrial membrane (Ψ IM~− 220 mV) [29], in the presence of sufficient oxygen, stable aerobic glycolysis (Warburg effect) is observed [30,31]. The difference in transmembrane mitochondrial potentials in tumor and normal cells (∆Ψ about 60 mV) leads to multiple (up to 1 × 10 3 times) accumulations of lipophilic cations in tumor cells, thereby conferring the property of selectivity [32]. ...
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The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylAmino)(Phenyl) Phosphonium halides (APPs) containing one, two, or three diethylamino groups was obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions (20 °C) and high yields (93–98%). The structure of APP was established by NMR and XRD. A high in vitro cytotoxicity of APPs against M-HeLa, HuTu 80, PC3, DU-145, PANC-1, and MCF-7 lines was found. The selectivity index is in the range of 0.06–4.0 μM (SI 17-277) for the most active APPs. The effect of APPs on cancer cells is characterized by hyperproduction of ROS and depolarization of the mitochondrial membrane. APPs induce apoptosis, proceeding along the mitochondrial pathway. Incorporation of APPs into lipid systems (liposomes and solid lipid nanoparticles) improves cytotoxicity toward tumor cells and decrease toxicity against normal cell lines. The IC50s of lipid systems are lower than for the reference drug DOX, with a high SI (30–56) toward MCF-7 and DU-145. APPs exhibit high selective activity against Gram-positive bacteria S. aureus 209P and B. segeus 8035, including methicillin-resistant S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead APP.
... The variant calls were classified into four categories to reflect the mode and functional effect of the mutations and then condensed at the gene level. The four categories included (1) MUT: miss-sense mutation, (2) LoF: loss of function variant, including frame-shift insertion/deletion and stopgain mutation, (3) CNV: copy number variation, and (4) FUSION: known driver gene fusion event. ...
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In radiomics research, the issue of different instruments being used is significant. In this study, we compared three correction methods to reduce the batch effects in radiogenomic data from fluorodeoxyglucose (FDG) PET/CT images of lung cancer patients. Texture features of the FDG PET/CT images and genomic data were retrospectively obtained. The features were corrected with different methods: phantom correction, ComBat method, and Limma method. Batch effects were estimated using three analytic tools: principal component analysis (PCA), the k -nearest neighbor batch effect test (kBET), and the silhouette score. Finally, the associations of features and gene mutations were compared between each correction method. Although the kBET rejection rate and silhouette score were lower in the phantom-corrected data than in the uncorrected data, a PCA plot showed a similar variance. ComBat and Limma methods provided correction with low batch effects, and there was no significant difference in the results of the two methods. In ComBat- and Limma-corrected data, more texture features exhibited a significant association with the TP53 mutation than in those in the phantom-corrected data. This study suggests that correction with ComBat or Limma methods can be more effective or equally as effective as the phantom method in reducing batch effects.
... The penetration of such cations through the hydrophobic layer of the lipid membrane is often the limiting stage of their accumulation in cells and mitochondria. In tumor cells characterized by hyperpolarized (in comparison with normal cells) mitochondrial membrane (ΨIM ~ -220 mV) [29], in the presence of sufficient oxygen, stable aerobic glycolysis (Warburg effect) is observed [30,31]. The difference in transmembrane mitochondrial potentials in tumor and normal cells (ΔΨ about 60 mV) leads to multiple (up to 1 × 10 3 times) accumulation of the lipophilic cations in tumor cells, thereby conferring the property of selectivity [32]. ...
Full-text available
The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylamino)(phenyl) phosphonium iodides (bromides) 1 containing one, two, or three diethylamino groups were obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions and high yields. The structure of compounds 1 was established by NMR and XRD. In vitro a high cytotoxicity against the lines M-Hela, HuTu 80, PC3, DU-145, PANC-1 and MCF-7 was found. Selectivity index are in the range of 0.06-4.0 M (SI 17-277) for the most active compounds. ROS production, mitochondrial localization and the process of cellular apoptosis were investigated. Decorated by 1 of lipid systems (liposomes and solid lipid nanoparticles) improve the cytotoxicity and a decrease in toxicity against normal cell lines. Compounds 1 induce apoptosis proceeding along the mitochondrial pathway. Aminophosphonium salts 1 also exhibit a high selective activity against the Gram-positive bacteria strains S. aureus 209P, B. segeus 8035, including methicillin-resistant strains of S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead compounds.
Background Tracheal, bronchus, and lung (TBL) cancer is the third most common and lethal type of cancer worldwide. Glucose metabolism disorders, as represented by high fasting plasma glucose (HFPG), increase the risk of development and worsen the prognosis of TBL cancer. This study aimed to evaluate the global disease burden of TBL cancer attributable to HFPG. Methods The TBL cancer burden attributable to HFPG was estimated based on a modeling strategy using the Global Burden of Disease Study 2019. The disease burden globally and by regions, countries, development levels, age groups, and sexes were also evaluated with the indicators of death, disability‐adjusted life years, years of life lost, and years lived with disability. The estimated annual percentage change (EAPC) was calculated by regression model to show the temporal trend. Results In 2019, approximately 8% of the total TBL cancer burden was attributable to HFPG. The HFPG‐attributable TBL cancer burden increased globally from 1990 to 2019 with the EAPC of 0.98% per year. The burden was positively associated with social development levels, and the global burden was three times greater in men than in women. HFPG‐attributable TBL cancer burden increased with age and peaked at above 70 years of age. Conclusions The findings highlight the effect and burden of glucose disorders, as represented by HFPG on TBL cancer burden. Integrated cancer prevention and control measures are needed, with control of glucose disorders as one of the key elements.
Drug synergy allows reduced dosing, side effects and tolerance. Optimization of drug synergy chemotherapy is fundamental in acute lymphocytic leukemia and other cancers. This study aimed to analyze the pharmacodynamic synergy between the anti-metabolite cytarabine and WEE1 inhibitor adavosertib on acute leukemia cell lines CCRF-CEM and Jurkat. In both cell lines analysis of concentration-inhibition curves of adavosertib-cytarabine combinations and synergy matrixes supported mutually synergistic drug interactions. Overall mean ( ± SD) synergy scores were higher in Jurkat than CCRF-CEM: Jurkat, ZIP 22.51 ± 1.1, Bliss 22.49 ± 1.1, HSA 23.44 ± 1.0, Loewe 14.16 ± 1.2; and, CCRF-CEM, ZIP 9.17 ± 1.9, Bliss 8.13 ± 2.1, HSA 11.48 ± 1.9 and Loewe 4.99 ± 1.8. Jurkat also surpassed CCRF-CEM in high-degree synergistic adavosertib-cytarabine interactions with mean across-models synergy values of ∼89.1% ± 2.9 for 63 nM cytarabine-97 nM adavosertib (91.4% inhibition synergy barometer). Combination sensitivity scores scatter plots confirmed combination's synergy efficacy. This combined approach permitted identification and prioritization of 63 nM cytarabine-97 nM adavosertib for multiple endpoints analysis. This combination did not affect PBMC viability, while exhibiting Jurkat selective synergy. Immunoblots also revealed Jurkat selective synergistically increased γH2AX phosphorylation, while CDC2 phosphorylation effects were attributed to adavosertib's WEE1 inhibition. In conclusion, the high synergistic efficacy combination of cytarabine (63 nM) and adavosertib (97 nM) was associated with remarkable alterations in metabolites related to the Krebs cycle in Jurkat. The metabolic pathways and processes are related to gluconeogenesis, amino acids, nucleotides, glutathione, electron transport and Warburg effect. All above relate to cell survival, apoptosis, and cancer progression. Our findings could pave the way for novel biomarkers in treatment, diagnosis, and prognosis of leukemia and other cancers.
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Previous studies suggest that metformin may exert a protective effect on cisplatin-induced cytotoxicity in cancer cells, and this finding has led to a caution for considering metformin use in the treatment of cancer patients. However, in this paper we provide the first demonstration that metformin synergistically augments cisplatin cytotoxicity in the esophageal squamous cancer cell line, ECA109, under glucose-deprivation conditions, which may be more representative of the microenvironment within solid tumors; this effect is very different from the previously reported cytoprotective effect of metformin against cisplatin in commonly used high glucose incubation medium. The potential mechanisms underlying the synergistic effect of metformin on cisplatin-induced cytotoxicity under glucose-deprivation conditions may include enhancement of metformin-associated cytotoxicity, marked reduction in the cellular ATP levels, deregulation of the AKT and AMPK signaling pathways, and impaired DNA repair function.
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Tumor tissue is composed of cancer cells and surrounding stromal cells with diverse genetic/epigenetic backgrounds, a situation known as intra-tumoral heterogeneity. Cancer cells are surrounded by a totally different microenvironment than that of normal cells; consequently, tumor cells must exhibit rapidly adaptive responses to hypoxia and hypo-nutrient conditions. This phenomenon of changes of tumor cellular bioenergetics, called “metabolic reprogramming”, has been recognized as one of 10 hallmarks of cancer. Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, accumulating evidence has revealed that tumor cells depend on mitochondrial metabolism as well as aerobic glycolysis. Remarkably, cancer-associated fibroblasts in tumor stroma tend to activate both glycolysis and autophagy in contrast to neighboring cancer cells, which leads to a reverse Warburg effect. Heterogeneity of monocarboxylate transporter expression reflects cellular metabolic heterogeneity with respect to the production and uptake of lactate. In tumor tissue, metabolic heterogeneity induces metabolic symbiosis, which is responsible for adaptation to drastic changes in the nutrient microenvironment resulting from chemotherapy. In addition, metabolic heterogeneity is responsible for the failure to induce the same therapeutic effect against cancer cells as a whole. In particular, cancer stem cells exhibit several biological features responsible for resistance to conventional anti-tumor therapies. Consequently, cancer stem cells tend to form minimal residual disease after chemotherapy and exhibit metastatic potential with additional metabolic reprogramming. This type of altered metabolic reprogramming leads to adaptive/acquired resistance to anti-tumor therapy. Collectively, complex and dynamic metabolic reprogramming should be regarded as a reflection of the “robustness” of tumor cells against unfavorable conditions. This review focuses on the concept of metabolic reprogramming in heterogeneous tumor tissue, and further emphasizes the importance of developing novel therapeutic strategies based on drug repositioning.
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Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.
It is long recognized that cancer cells display increased glucose uptake and metabolism. In a rate-limiting step for glucose metabolism, the glucose transporter (GLUT) proteins facilitate glucose uptake across the plasma membrane. Fourteen members of the GLUT protein family have been identified in humans. This review describes the major characteristics of each member of the GLUT family and highlights evidence of abnormal expression in tumors and cancer cells. The regulation of GLUTs by key proliferation and pro-survival pathways including the phosphatidylinositol 3-kinase (PI3K)-Akt, hypoxia-inducible factor-1 (HIF-1), Ras, c-Myc and p53 pathways is discussed. The clinical utility of GLUT expression in cancer has been recognized and evidence regarding the use of GLUTs as prognostic or predictive biomarkers is presented. GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3, GLUT5 and others are inhibited to decrease cancer growth.
Invasiveness is a hallmark of aggressive cancer like malignant melanoma, and factors involved in acquisition or maintenance of an invasive phenotype are attractive targets for therapy. We investigated melanoma phenotype modulation induced by the metastasis-promoting microenvironmental protein S100A4, focusing on the relationship between enhanced cellular motility, dedifferentiation and metabolic changes. In poorly motile, well-differentiated Melmet 5 cells, S100A4 stimulated migration, invasion and simultaneously down-regulated differentiation genes and modulated expression of metabolism genes. Metabolic studies confirmed suppressed mitochondrial respiration and activated glycolytic flux in the S100A4 stimulated cells, indicating a metabolic switch towards aerobic glycolysis, known as the Warburg effect. Reversal of the glycolytic switch by dichloracetate induced apoptosis and reduced cell growth, particularly in the S100A4 stimulated cells. This implies that cells with stimulated invasiveness get survival benefit from the glycolytic switch and therefore, become more vulnerable to glycolysis inhibition. In conclusion, our data indicates that transition to the invasive phenotype in melanoma involves dedifferentiation and metabolic reprogramming from mitochondrial oxidation to glycolysis, which facilitates survival of the invasive cancer cells. Therapeutic strategies targeting the metabolic reprogramming may therefore be effective against invasive phenotype. Copyright © 2015. Published by Elsevier Ireland Ltd.
Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.