www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 19
Important roles of P2Y receptors in the inammation and cancer
of digestive system
Han-Xing Wan1, Jian-Hong Hu1, Rei Xie1, Shi-Ming Yang1 and Hui Dong1,2
1 Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
2 Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, California,
Correspondence to: Hui Dong, email: firstname.lastname@example.org
Keywords: P2Y receptors, digestive inammation, digestive cancer
Received: November 04, 2015 Accepted: February 05, 2016 Published: February 19, 2016
Purinergic signaling is important for many biological processes in humans.
Purinoceptors P2Y are widely distributed in human digestive system and dierent
subtypes of P2Y receptors mediate dierent physiological functions from metabolism,
proliferation, dierentiation to apoptosis etc. The P2Y receptors are essential in
many gastrointestinal functions and also involve in the occurrence of some digestive
diseases. Since dierent subtypes of P2Y receptors are present on the same cell of
digestive organs, varying subtypes of P2Y receptors may have opposite or synergetic
functions on the same cell. Recently, growing lines of evidence strongly suggest the
involvement of P2Y receptors in the pathogenesis of several digestive diseases. In
this review, we will focus on their important roles in the development of digestive
inammation and cancer. We anticipate that as the special subtypes of P2Y receptors
are studied in depth, specic modulators for them will have good potentials to become
promising new drugs to treat human digestive diseases in the near future.
Purinoceptors are generally divided into P1
receptors which main ligand is adenosine, and P2 receptors
which main ligands are nucleotides. Based on their
signaling properties, P2 receptors are further subdivided
into ionotropic P2X receptors that are nucleotide-gated
ion channels and metabotropic P2Y receptors that are G
protein-coupled receptors (GPCRs). P2Y receptors are
consist of eight subtypes: ve Gq/G11-coupled subtypes
(P2Y1, P2Y2 , P2Y4, P2Y6 and P2Y11), usually
activating phospholipase C-IP3 pathway that modulates
endoplasmic reticulum calcium release, and three Gi/o-
coupled subtypes (P2Y12, P2Y13 and P2Y14), mainly
inhibiting adenylyl cyclase to regulate cyclic AMP/
protein kinase A (PKA) [1-2]. At present, all eight P2Y
receptor subtypes have been cloned in mammalian .
Different P2Y receptor subtypes are activated by different
nucleotides. ADP has been claimed to be selective agonist
of P2Y1, P2Y12 and P2Y13 receptors; however, UTP
predominantly binds to P2Y2 and P2Y4 receptors, and
to a lesser extent to P2Y6 receptors which preferential
agonist is UDP. P2Y14 receptors are mainly activated
by UDP-glucose and other UDP-sugars, or by UDP .
In recent decades, a growing line of evidence suggests
the involvements of P2Y receptors in the pathogenesis
of human diseases, and different subtypes of P2Y
receptors mediate various pathophysiological processes,
ranging from metabolism, proliferation, differentiation
to apoptosis. Recent studies also demonstrate that
P2Y receptors play important roles in the regulation of
physiological functions and pathological processes in
the digestive system. In this review, we will focus on the
pathophysiological roles of P2Y receptors in digestive
inammation and cancer.
PHYSIOLOGICAL FUNCTIONS OF
P2Y RECEPTORS IN THE DIGESTIVE
P2Y receptors are widely expressed in digestive
organs and their functions vary from neurotransmission,
gland secretion, contraction and relaxation of smooth
muscle to carbohydrate and lipid metabolism in the
digestive system. In accordance with evidence, we rst
highlight physiological roles of P2Y receptors in the
esophagus, stomach, liver, pancreas, and colon (Figure 1).
The P2Y receptors are functionally expressed in the
esophagus to play an important role in the regulation of
esophageal motility. In human and porcine esophagus,
P2Y1 receptors mediate lower esophageal sphincter
(LES) relaxation by regulating neurotransmission [5-6].
P2Y1 receptors also mediate contraction of the circular
smooth muscle layer in porcine esophagus . Electrical
eld stimulation (EFS)-induced contractions is mediated
through P2Y receptors in cat esophageal smooth muscle
. Feline esophageal contraction is preferentially
mediated by P2Y receptors coupled to Gαi3 and Gαq
proteins, which activate PLCβ, subsequently increase
intracellular Ca2+ and activate PKC .
Although gastric acid secretion is mainly regulated
by P1 adenosine receptors , P2Y receptors may
also regulate gastric acid secretion, gastric contraction,
relaxation and neurotransmission. However, the specic
receptor subtypes of P2Y receptors involved and their
underlying mechanisms still need further investigation.
ATP selectively inhibits histamine-stimulated gastric
acid secretion from rabbit parietal cells by acting on P2Y
receptors . UTP and UDP can induce contraction of
gastric smooth muscle through activation of P2Y receptors
. ATP also induces contraction of gastric smooth
muscle in guinea pig via activation of P2Y receptors .
At least two subtypes of P2Y purinoceptors are involved
in gastric contraction in guinea-pig and are related to the
elevation of intracellular Ca2+ . Finally, ATP may
regulate NANC inhibitory neurotransmission in rat pyloric
sphincter through acting on P2Y receptors .
Several P2Y receptor subtypes regulate hepatic
physiological functions, such as carbohydrate metabolism,
lipid metabolism and proliferation [16-17]. P2Y1 receptors
induce glycogen phosphorylase of rat hepatocyte by
raising intracellular calcium concentrations but inhibiting
cyclic AMP accumulations . P2Y2 receptors in
human hepatocytes regulate both glycogen metabolism
and proliferation-associated responses through Ca2+ and
MAPK pathways , and induce ERK phosphorylation,
Egr-1 expression, and cyclins and cell cycle progression,
which are essential for efcient hepatocyte proliferation
. P2Y2 receptors also mediate extracellular ATP-
induced c-jun N-terminal kinase signaling and cell cycle
progression to promote hepatocellular proliferation .
P2Y13 receptors modulate reverse cholesterol transport
by increasing hepatic HDL cholesterol uptake, overall
hepatocyte cholesterol content, and biliary output [22-24].
P2Y1, 2, 4, 6, 11, 12 and 13 receptor subtypes have
been identied in INS-1βcells, mouse, rat and human
pancreaticβcells [25-26]. Activation of P2Y receptors
inβcells is conrmed to participate in the regulation of
insulin secretion, glucose metabolism and an increase in
concentration . Glucose stimulation
triggers exocytosis of insulin and ATP through activation
of P2Y1 receptors to result in PLC activation and DAG
production in MIN6 mouse pancreaticβcells . P2Y1
and P2Y6 receptors in MIN6 cells induce intracellular
calcium release and insulin secretion, and prevent TNF-α
induced βcells apoptosis . Stimulation of P2Y13
receptors in pancreatic βcells inhibits insulin secretion via
calcium inux and inhibition of cyclic AMP production
. High glucose and free fatty acids can also induce
β cells apoptosis through stimulating P2Y13 to activate
apoptotic pathways .
Large numbers of studies in animals and humans
demonstrate that P2Y1 receptors mediate NANC
inhibitory transmission of intestinal smooth muscle in
mice through release of ATP and NO . Activation
of P2Y1 receptors can induce nerve-mediated relaxation
via inhibitory neuromuscular transmission in human
intestines, guinea pig small intestine and rat colon [32-35].
Endogenous nucleotides acting on P2Y1, 2, 4 receptors
evoke intestinal Cl− secretion . The activation of P2Y2
and P2Y4 receptors stimulate Cl− secretion in small and
large intestines. Basolateral UTP-induced Cl− secretion in
jejunum was partially reduced in P2Y2 knockout (40%)
and P2Y4 knockout (60%) null mice . Activation of
P2Y2 receptors induces duodenal mucosal bicarbonate
secretion via both intracellular Ca2+ release and
extracellular Ca2+ entry through store-operated channels
. Stimulation of luminal P2Y2 and P2Y4 receptors
lead to K+ secretion in mouse distal colonic mucosa
; however, activation of basolateral P2Y6 receptors
on rat colonic enterocytes induces NaCl secretion via a
synergistic increase of [Ca2+]i and cyclic AMP .
P2Y RECEPTORS IN DIGESTIVE
Over the past decades, many studies have
highlighted fundamental roles of P2Y receptors in
inammatory diseases, particularly P2Y2, 6, 12 receptors
have been well studied, such as P2Y2 receptor agonists
can treat cystic borosis, and promote wound healing
and leukocyte functions [4, 41-45]. Whereas, P2Y2
receptors have ambivalent functions, such as promoting
chronic inammatory states and brotic remodeling [46-
48]. However, in inammation of the digestive system,
the studies of P2Y receptors are mainly concentrated on
the liver and colon. The involvements of P2Y receptors
in the inammation of other digestive organs, such
as esophagitis, gastritis and pancreatitis, are poorly
understood and rarely presented in the literatures.
During inammatory responses, endogenous release
of ATP in the liver can activate purinergic P2 receptors.
It was found that large amounts of ATP released from
the liver increased the expression of P2Y2 receptors
in concanavalin A-induced model of acute hepatitis in
C57BL/6 mice. Liver damage and necrosis are largely
decreased in C57BL/6 wild-type mice injected with
suramin, an inhibitor of P2Y receptors, or in P2Y2
receptors knockout mice, in which acetaminophen-
induced liver damage is also alleviated. P2Y2 receptors
can promote neutrophil inltration, regulate cell survival,
and promote tumor necrosis factor-mediated cell death,
supporting the view that activation of P2Y2 receptors
stimulates the recruitment of neutrophils into the liver to
cause hepatocyte death .
Hepatic stellate cells play an important role in
formation of liver brosis and liver cirrhosis. ATP
increases intracellular Ca2+ in hepatic stellate cells, which
is inhibited by suramin. Interestingly, P2Y2 and P2Y4
receptors are expressed in quiescent hepatic stellate
cells, whereas P2Y6 receptors are expressed in activated
hepatic stellate cells. The activated hepatic stellate cells
express the ectonucleotidase nucleoside triphosphate
diphosphohydrolase-2 (NTPDase-2) that colocalizes with
activated HSC in CCl4-induced cirrhosis. UDP regulates
transcription of procollagen-1 in activated HSC via P2Y
receptors activation, which is partially inhibited by the
P2Y receptors inhibitor suramin, suggesting P2Y receptors
may be attractive targets to prevent/treat liver brosis
. When macrophages in kupffer cells of the liver are
activated by various factors, such as lipopolysaccharide
(LPS), they produce various cytokines and chemokines
Figure 1: The physiological functions of P2Y receptors in digestive system. Different subtypes of P2Y receptors are expressed
in human esophagus, stomach, liver, pancreas and colon. They play different roles in the regulation of physiological processes, such as
neurotransmission, ion transports, metabolism, proliferation and apoptosis, muscle contraction and relaxation in the digestive organs.
to play important roles in hepatitis and liver brosis.
P2Y2, 5, 6, 12, 13 receptors are strongly expressed in
the liver kupffer cells of C57BL/6 mice (KUP5 cells).
After stimulation with LPS, KUP5 cells produce IL-6 and
TNF-α. Non-selective P2 receptor antagonist, suramin,
and P2Y13 receptors selective antagonist, MRS2211,
markedly inhibit LPS-induced IL-6 increase in KUP5
cells, whereas both suramin and MRS2211 do not inhibit
LPS-induced TNF-α production, suggesting that P2Y13
and other P2Y receptors may be involved in LPS-induced
IL-6 production in Kuffer cells and liver inammation
Figure 2: P2Y receptors-mediated Ca2+ signaling in proliferation or apoptosis of digestive cancer cells. Stimulation of
Gq/G11-coupled P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) activates PLC/IP3 pathway to induce intracellular calcium
release from the endoplasmic reticulum (ER). An increase in intracellular calcium concentrations would increase the proliferation or
apoptosis of different digestive cancer cells.
Intestinal inammation can upregulate mRNA
expression of P2Y2 and P2Y6 receptors in the colonic
mucosa of colitic mice. The mRNA of P2Y2 and P2Y6
receptors are increased in both Crohn’s and ulcerative
colitis of intestinal human samples compared with
noninamed tissues. The mRNA expression of P2Y2
receptors is also increased in Caco-2 and IEC-6 cells
during intestinal inammation, but it is unknown how
inammation up-regulates expression of P2Y2 receptors.
ATP or UTP stimulation of P2Y2 receptors in intestinal
epithelial cells increases ICAM-1 expression and promotes
transepithelial migration and adhesion of neutrophils and
macrophage to the apical surface of IEC. In addition, ATP
or UTP facilitates the migration of neutrophil-like PLB-
985 cells and macrophage across the Caco-2 monolayer
and promotes macrophage-like U-937 cells adhere to
IEC monolayers. CD68+ macrophage inltrates from
the colonic epithelium and presents at the apical surface
of colonocytes during intestinal inammation. P2Y2
receptors mediate neutrophil adhesion to the surface
of IEC need presence of adherent macrophage. This
investigation is helpful to identify potential therapeutic
targets to treat inammatory bowel diseases . Recent
studies found that NF-κB p65 could regulate P2Y2
receptors transcription, and activation of P2Y2 receptors
by UTP increased both cyclooxygenase-2 (COX-2)
expression and PGE2 release in IEC . Further studies
showed the effects of CCAAT/enhancer-binding proteinβ
(C/EBPβ) and NF-κB p65 on P2Y2 receptor transcription
are synergistic during inammation in IEC . In the
enteric nervous system, ATP has long been established
as an inhibitory neurotransmitter, 75% of Hirschsprung’s
disease patients, aganglionosis is conned to the
intestine. The expression of P2Y1 and P2Y2 receptors
are absent from the submucosal and myenteric plexuses
of aganglionic tissue compared to ganglionic tissue and
normal controls. The deciency of P2Y receptors in
ganglionic intestine in Hirschsprung’s disease suggests
the absence of the inhibitory neurotransmitter, ATP. This
explains the contracted state of the aganglionic gut in
Hirschsprung’s disease .
The expression of P2Y6 receptors is enhanced
by inammation with TNF-α and IFN-γ both in IEC-
6 and Caco-2/15 cells. In Caco-2/15 cells, stimulation
P2Y6 receptors by UDP results in an increased
expression and release of CXCL8, partially depending
on ERK1/2 phosphorylation. UDP also increases
ERK1/2 phosphorylation of IEC-6 cells, suggesting
the involvement of P2Y6 receptors . Indeed, UDP
stimulation of P2Y6 receptors promotes CXCL8
transcription through ERK1/2 activation and the AP-1
complex of transcription factors, aggravating colitis-like
disease in mice by stimulating neutrophil recruitment
at the site of inammation. CXLC8 gene expression
is regulated at the transcriptional level by mediating
ERK1/2-dependent phosphorylation of c-fos in IEC
through P2Y6 receptors activation. P2Y6 regulation of
CXCL8 expression requires PKCδactivation upstream of
the signaling pathway composed of MEK1/2-ERK1/2 and
c-fos . Previous reports revealed that T cells play an
important role in the pathogenesis of IBD and extracellular
nucleotides can regulate colonic epithelial cell damage
during inammation. Interestingly, UDP, P2Y6 receptors
selective agonist, activates peripheral T cells and increases
mRNA levels of P2Y6 receptors, and raises intracellular
calcium concentration. Although P2Y6 receptors are
expressed in human T cell inltrating IBD,the roles of
P2Y6 receptors in the pathogenesis of IBD need further
P2Y RECEPTORS IN DIGESTIVE
Different subtypes of P2Y receptors are expressed
in many cancer cells and tissues to be likely involved in
cancer development, such as P2Y receptors in melanoma
, skin squamous cell carcinoma , lung cancer
[61-62], prostate cancer [63-66], glioma [67-68], breast
cancer [69-75], ovarian cancer , and haematological
malignancies , etc. Recent growing lines of evidence
suggest an important role of P2Y receptors in digestive
tumorigenesis. Different subtypes of P2Y receptors are
present in cancer cells and primary cancer tissues of
digestive system; however, the mechanisms by which
these receptors play in the devolvement and progression
of cancers are still poorly understood. The involvement of
P2Y receptors in digestive cancer is mainly investigated
in esophageal cancer, hepatocellular carcinoma, biliary
cancer, pancreatic cancer and colorectal cancer, which are
summarized in Table 1 and Figure 2. Although expression
and function of P2Y receptors are well documented in
normal human and animal stomach, their involvements in
the pathogenesis of gastric cancer have not been explored
The squamous esophageal cancer cell line, Kyse-140
cells express mRNA of P2X4, P2X5, and P2Y2 receptors,
but not P2X1 and P2X7 receptors that are mainly
associated with apoptosis. The mRNA of P2Y2 and P2X4
receptors are also found in biopsies of human squamous
esophageal cancer; however, in accordance with the Kyse-
140 cells, the mRNA of the P2X1 and P2X7 receptors are
not expressed in human squamous esophageal cancer
biopsy. Although mRNA of P2Y2 and P2X4 receptors was
found in both Kyse-140 and esophageal primary culture
cells, only P2Y2 receptors protein specic uorescence
was detected in the membrane of the Kyse-140 and
esophageal primary culture cells. ATP, UTP and ATPγS,
responding to P2Y2 receptors activation, result in an
increase of intracellular Ca2+ levels. Incubation of Kyse-
140 cells with the phospholipase C inhibitor U73122
dose-dependently inhibits ATP-induced intracellular Ca
level, suggesting that P2Y2 receptors mediate intracellular
Ca2+ via phospholipase C (PLC) activation in Kyse-
140 cells. Extracellular ATP as well as ATP analogue
dose-dependently increase the proportion of cells in the
S-phase of the cell cycle in return inhibiting proliferation
of primary cell cultures of human esophageal cancer
as well as Kyse-140; however, only ATP but not ATP
analogue dose-dependently induces caspase-3 activity and
increases in apoptosis of Kyse-140 cells through activation
of P2Y2 receptors . Together, these ndings suggest
that purinergic nucleotides may be tumor preventers
through P2Y2 receptors/PLC/Ca
signaling in squamous
P2Y1 purinergic receptors were found to play a
role in the response of hepatocellular carcinoma (HCC)
cells to osmotic swelling and involved in the volume-
regulatory response . However, in HCC cells, copper
inhibits thapsigargin-sensitive Ca2+ stores by acting
P2Y2 receptors to lead to inhibition of regulatory volume
decrease (RVD) . The mRNA and protein levels of
P2Y13 receptors are conrmed in Huh-7 hepatoma
cells that can release ATP when exposed to hypotonicity
medium. On the other hand, ADP can activate P2Y13
receptors to potentiate volume regulatory decrease (RVD)
and then mediate cell metabolism .
A recent study showed that both mRNA and protein
expression levels of P2Y2 receptors were dramatically
higher in native human HCC and human HCC cell lines
compared with human normal hepatocytes. Extracellular
nucleotides-induced intracellular Ca
increase is markedly
higher in human HCC cells than normal hepatocytes.
Activation of P2Y2 receptors signicantly promotes
proliferation and migration of HCC cells and volume
growth of HCC in nude mice through store-operated
calcium channels (SOCs)-mediated Ca2+ signaling .
Insulin and ATP induce a dose-dependent increase in
p44/42 MAPK phosphorylation in rat HCC cells and
chelation of extracellular Ca2+ with EGTA diminishes ATP-
and insulin-induced p44/42 MAPK phosphorylation. Patch
clamp electrophysiology and uorescence microscopy
showed that insulin and ATP induced monophasic
Table 1: Involvement of P2Y receptors in various types of digestive cancer
Cancer types Tissue
Kyse-140 P2Y2 PLC/Ca2+ anti-proliferative
cell metabolism [79-81]
BEL-7404 P2Y2 Ca2+
MAPK glucose metabolism 
huh-7 P2Y1,2,4,6 Ca2+ unknown 
Biliary cancer Mz-Cha-1 P2Y1,2,4,6 Ca2+ unknown 
PANC-1 P2Y1,2, 6 PLC
IP3/PKC pro-proliferative [86-87]
HT-29 P2Y2 ECAR tumor cell metabolism 
P2Y2,4 Ca2+ anti-proliferative
Caco2 P2Y1,2,4,6,11,12 Ca2+ pro-proliferative
HT-29 P2Y2 ERK
Caco2 P2Y2,4 Ca2+
and multiphasic changes in membrane potential and
intracellular Ca2+ in HCC cells. Therefore, insulin and
ATP effects are synergistic to regulate glucose metabolism
of HCC cells . Although the mRNA of P2Y1, P2Y2,
P2Y4 and P2Y6 receptors were detected in HepG2 and
HuH-7 cells, P2Y1 and P2Y6 receptor agonists, ATP and
UDP, did not alter intracellular Ca2+, suggesting that these
receptors are not expressed at functional levels. However,
UTP through activation of P2Y2 and P2Y4 receptors can
mobilize internal Ca2+ via inositol 1,4,5-trisphosphate (IP3)
. Therefore, these P2Y receptors may play major roles
in the pathogenesis of HCC.
Although the mRNAs for P2Y1, P2Y2, P2Y4
and P2Y6 purinergic receptors subtypes are found in
biliary epithelial cancer cells (Mz-Cha-1), but only
P2Y2 receptors are present at the protein level. Not
only extracellular ATP dose-dependently results in
an intracellular Ca2+ increase, but also UTP produces
a similar Ca2+ response and cross-desensitation. ATP
induces cytosolic and nuclear Ca
transients . To date,
only expression of P2Y receptors is observed in biliary
epithelial cancer cells, however, the roles of P2Y receptors
in biliary cancer need further investigation.
P2Y receptors, especially P2Y1, P2Y2 and P2Y6
receptors are highly expressed in PANC-1, a duct epithelial
cell derived from human primary pancreatic cancer cells.
P2Y1 and P2Y6 proteins were also found in PANC-1 cells.
ADP activation of P2Y1 receptors and UDP acting P2Y6
receptors increase proliferation of PANC-1 cell through
PLC/IP3/PKC pathway. This proliferative action of P2Y
receptors may potentially apply to recover pancreatic
duct epithelial damage by physiological or pathological
processes . UTP or P2Y2 receptor selective agonist
MRS2768 can increase proliferation of PANC-1, which
is signicantly decreased by P2Y receptor antagonist
suramin and siRNA against P2Y2 receptors. UTP/P2Y2
receptor regulation of pancreatic cell proliferation depends
/PKC and phosphorylation of Akt . In INS-
1 cells and rat pancreatic islets, ATP at low concentrations
increases insulin release via P2Y receptors and PLC;
however, ATP at high concentrations inhibits insulin
release after metabolizing to adenosine . So far, the
roles of P2Y receptors in pancreatic cancer are poorly
understood and need lucubrating.
P2Y2 and P2Y4 receptors are overexpressed
in human colon cancer compared with normal colon
tissues although their functional signicance need
further studies . Immunocytochemistry and western
blot analysis also demonstrate the protein expression of
P2Y2 receptors in HT-29 human colon carcinoma cells.
ATP or UTP elicits a biphasic effect of extracellular
acidication rate by activating P2Y2 receptors in HT-
29 cells, but effects of UTP or ATP are resistant to
suramin, suggesting that agonists of purinoceptors may
affect tumor cell metabolism . The mRNA of P2Y2
receptors is expressed in two colorectal carcinoma cell
lines (HT29, Colo320DM) and short-term stimulation of
P2Y2 receptors cause both intracellular Ca2+ release and
transmembrane Ca2+ inux, and a subsequent increase
in cyclic AMP. This effect is inhibited by BAPTA-AM.
Prolonged stimulation of P2Y2 receptors induces a time-
dependent increase in apoptosis in both cell lines and
causes a dose-dependent inhibition of cell proliferation
up to 85% (Colo320 DM) or 64% (HT29). Chelating
[Ca2+]i with BAPTA-AM almost completely abolishes
this effect. Moreover, forskolin or cyclic AMP derivatives
cause a rise in intracellular cyclic AMP and lead to
synergistic anti-proliferative effect in both cell lines. This
nding demonstrates P2Y2 receptors play major roles in
anti-proliferative and apoptosis-inducing in colorectal
carcinoma cell lines . The primary cell cultures of
human colorectal carcinomas and HT29 cell line express
functional P2U-receptors (P2Y2 and P2Y4). ATP or UTP
at micromolar concentrations leads to a rapid biphasic
increase of [Ca
and cross-desensitization between two
nucleotides. P2U-receptor agonist ATP derivative ATP-γ-S
inhibits proliferation and induces apoptosis of HT 29 cells
Two human colorectal carcinoma cell lines (HCT8
and Caco-2) express mRNA of P2Y1, 2, 4, 6, 11, 12
receptors and proteins of P2Y1 and P2Y2 receptors. ATP,
at high concentrations, induces apoptosis through P2Y1
receptors; conversely, ATP, at lower concentrations,
and UTP stimulates proliferation of human colorectal
carcinoma cells, probably acting on P2Y2 receptors.
UTP can trigger calcium inuxes through either P2Y2 or
P2Y4 receptors, which is inhibited by suramin. Therefore,
stimulation of purinergic receptors may contribute to the
modulation of epithelial carcinoma cell proliferation and
apoptosis . Ursolic acid could inhibit proliferation of
HT29 and induce apoptosis via P2Y2 receptors-mediated
inhibition of ERK phosphorylation and activation of p38
MAPK pathway [95-96]. The mRNA of P2Y2 and P2Y4
receptors is found in Caco-2 cells. ATP, UTP and UDP
increase phosphorylation of MAPK by stimulating P2Y
receptors, probably through subtypes of P2Y2, P2Y4,
P2Y6 and P2Y11 receptors. ATP increases proliferation
of Caco-2 cells via activation of P2Y purinergic receptors
[97-98]. On the contrary, higher concentrations (1-10 mM)
of extracellular ATP or the unhydrolyzed ATP analogue
5’-adenylyimido-diphosphate (AMP-PNP), suppress
Caco-2 cell proliferation arresting cells cycling at the S
phase by inhibiting PKC, ERK and MAP kinase . The
sustained activation of P2 receptors by ATP may lead to
IL-8 secretion from human colorectal epithelial cells and
may play an important role in tumor progression as well
as in the pathology of IBD .
Growing lines of evidence suggest that P2Y
receptors are involved in inammation-associated
diseases of liver and colon. P2Y receptors can also
regulate metabolism, proliferation, differentiation and
apoptosis of digestive cancer cells and tissues. It has
been demonstrated that different P2Y receptor subtypes
are present on the same cell and that various subtypes of
receptors may produce opposite functions. Such as HCT8
and Caco-2 cells express P2Y1, P2Y2, P2Y4, P2Y6,
P2Y11, and P2Y12 receptors. Lower concentrations of
ATP and UTP stimulate proliferation of these cells via
P2Y2 receptors activation, but high concentrations of
ATP induce apoptosis and anti-proliferation through
P2Y1 and P2X7 receptors. This suggests that the control
of cell proliferation by extracellular nucleotides might
be regulated by a crucial balance of the activities of the
receptor subtypes. The subtypes of P2Y receptors as new
therapeutic targets for drug discovery to treat digestive
diseases may have extensive clinical signicance. We
therefore anticipate that as these subtypes of P2Y receptors
in digestive organs are further studied, their specic
modulators may become promising new drugs to treat
digestive diseases, such as inammation and cancer in the
GPCRs:G protein-coupled receptors; PKA: protein
kinase A; LES: lower esophageal sphincter; NTPDase-2:
nucleoside triphosphate diphosphohydrolase-2; LPS:
lipopolysaccharide; COX-2: cyclooxygenase-2; IBD:
inammatory bowel diseases; RVD: volume regulatory
decrease; SOCs: store-operated calcium channels; Mz-
Cha-1: biliary epithelial cancer cells; AMP-PNPATP:
analogue 5’-adenylyimido-diphosphate; HCC:
hepatocellular carcinoma; PLC: phospholipase C; IP3:
supported by the National Natural Science
Foundation of China ( No.31371167 and No.81570477 to
CONFLICTS OF INTEREST
The authors declare no conicts of interest.
1. Abbracchio MP, Burnstock G, Verkhratsky A and
Zimmermann H. Purinergic signalling in the nervous
system: an overview. Trends in Neurosciences. 2009;
2. Stagg J and Smyth MJ. Extracellular adenosine triphosphate
and adenosine in cancer. Oncogene. 2010; 29:5346-5358.
3. White N and Burnstock G. P2 receptors and cancer. Trends
Pharmacol Sci. 2006; 27:211-217.
4. Idzko M, Ferrari D and Eltzschig HK. Nucleotide signalling
during inammation. Nature. 2014; 509:310-317.
5. Lecea B, Gallego D, Farre R, Opazo A, Auli M, Jimenez
M and Clave P. Regional functional specialization and
inhibitory nitrergic and nonnitrergic coneurotransmission
in the human esophagus. Am J Physiol Gastrointest Liver
Physiol. 2011; 300:G782-794.
6. Farre R, Auli M, Lecea B, Martinez E and Clave P.
Pharmacologic characterization of intrinsic mechanisms
controlling tone and relaxation of porcine lower esophageal
sphincter. J Pharmacol Exp Ther. 2006; 316:1238-1248.
7. Lecea B, Gallego D, Farre R and Clave P. Origin and
modulation of circular smooth muscle layer contractions
in the porcine esophagus. Neurogastroenterol Motil. 2012;
8. Cho YR, Jang HS, Kim W, Park SY and Sohn UD. P2X and
P2Y Receptors Mediate Contraction Induced by Electrical
Field Stimulation in Feline Esophageal Smooth Muscle.
Korean J Physiol Pharmacol. 2010; 14:311-316.
9. Kwon TH, Jung H, Cho EJ, Jeong JH and Sohn UD. The
Signaling Mechanism of Contraction Induced by ATP and
UTP in Feline Esophageal Smooth Muscle Cells. Mol Cells.
10. Burnstock G. Purinergic signalling in the gastrointestinal
tract and related organs in health and disease. Purinergic
Signalling. 2014; 10:3-50.
11. Gil-Rodrigo CE, Bergaretxe I, Carou M, Galdiz B, Salgado
C and Ainz LF. Inhibitory action of extracellular adenosine
5’-triphosphate on parietal cells isolated from rabbit gastric
mucosa. Gen Physiol Biophys. 1996; 15:251-264.
12. Yuan WS, Wang ZY, Li JJ, Li D, Liu DL, Bai G, Walsh MP,
Gui Y and Zheng XL. Uridine adenosine tetraphosphate
induces contraction of circular and longitudinal gastric
smooth muscle by distinct signaling pathways. Iubmb Life.
13. Jin Z, Guo HS, Xu DY, Hong MY, Li XL and Xu WX.
[Effects of purinergic analogues on spontaneous contraction
and electrical activities of gastric antral circular muscle in
guinea-pig]. Sheng Li Xue Bao. 2004; 56:678-684.
14. Ahn SC, Xu WX, So I, Kim KW and Kang TM. Effects of
purinergic agonists on mechanical and electrical activities
of gastric smooth muscle of guinea-pig. J Smooth Muscle
Res. 1995; 31:407-410.
15. Soediono P and Burnstock G. Contribution of ATP and
nitric oxide to NANC inhibitory transmission in rat pyloric
sphincter. Br J Pharmacol. 1994; 113:681-686.
16. Dixon CJ, Woods NM, Webb TE and Green AK. Evidence
that rat hepatocytes co-express functional P2Y1 and P2Y2
receptors. Br J Pharmacol. 2000; 129:764-770.
17. Dixon CJ. Evidence that 2-methylthioATP and
2-methylthioADP are both agonists at the rat hepatocyte
P2Y(1) receptor. Br J Pharmacol. 2000; 130:664-668.
18. Dixon CJ, Hall JF, Webb TE and Boarder MR. Regulation
of rat hepatocyte function by P2Y receptors: Focus on
control of glycogen phosphorylase and cyclic AMP
by 2-methylthioadenosine 5 ‘-diphosphate. Journal of
Pharmacology and Experimental Therapeutics. 2004;
19. Dixon CJ, White PJ, Hall JF, Kingston S and Boarder
MR. Regulation of human Hepatocytes by P2Y receptors:
Control of glycogen phosphorylase, Ca2+, and mitogen-
activated protein kinases. Journal of Pharmacology and
Experimental Therapeutics. 2005; 313:1305-1313.
20. Tackett BC, Sun HD, Mei Y, Maynard JP, Cheruvu S,
Mani A, Hernandez-Garcia A, Vigneswaran N, Karpen SJ
and Thevananther S. P2Y2 purinergic receptor activation
is essential for efcient hepatocyte proliferation in
response to partial hepatectomy. American Journal of
Physiology-Gastrointestinal and Liver Physiology. 2014;
21. Thevananther S, Sun HD, Li D, Arjunan V, Awad SS,
Wyllie S, Zimmerman TL, Goss JA and Karpen SJ.
Extracellular ATP activates c-jun N-terminal kinase
signaling and cell cycle progression in hepatocytes.
Hepatology. 2004; 39:393-402.
22. Vaughn BP, Robson SC and Longhi MS. Purinergic
Signaling in Liver Disease. Digestive Diseases. 2014;
23. Fabre AC, Malaval C, Ben Addi A, Verdier C, Pons V,
Serhan N, Lichtenstein L, Combes G, Huby T, Briand
F, Collet X, Nijstad N, Tietge UJF, Robaye B, Perret
B, Boeynaems JM, et al. P2Y13 Receptor is Critical for
Reverse Cholesterol Transport. Hepatology. 2010; 52:1477-
24. Blom D, Yamin TT, Champy MF, Selloum M, Bedu E,
Carballo-Jane E, Gerckens L, Luell S, Meurer R, Chin J,
Mudgett J and Puig O. Altered lipoprotein metabolism in
P2Y(13) knockout mice. Biochimica Et Biophysica Acta-
Molecular and Cell Biology of Lipids. 2010; 1801:1349-
25. Petit P, Lajoix AD and Gross R. P2 purinergic signalling
in the pancreatic beta-cell: control of insulin secretion and
pharmacology. Eur J Pharm Sci. 2009; 37:67-75.
26. Lugo-Garcia L, Filhol R, Lajoix AD, Gross R, Petit P and
Vignon J. Expression of purinergic P2Y receptor subtypes
by INS-1 insulinoma beta-cells: a molecular and binding
characterization. Eur J Pharmacol. 2007; 568:54-60.
27. Farret A, Vignaud M, Dietz S, Vignon J, Petit P and Gross
R. P2Y purinergic potentiation of glucose-induced insulin
secretion and pancreatic beta-cell metabolism. Diabetes.
2004; 53 Suppl 3:S63-66.
28. Wuttke A, Idevall-Hagren O and Tengholm A. P2Y(1)
receptor-dependent diacylglycerol signaling microdomains
in beta cells promote insulin secretion. Faseb Journal. 2013;
29. Balasubramanian R, Ruiz de Azua I, Wess J and Jacobson
KA. Activation of distinct P2Y receptor subtypes stimulates
insulin secretion in MIN6 mouse pancreatic beta cells.
Biochem Pharmacol. 2010; 79:1317-1326.
30. Amisten S, Meidute-Abaraviciene S, Tan C, Olde B,
Lundquist I, Salehi A and Erlinge D. ADP mediates
inhibition of insulin secretion by activation of P2Y13
receptors in mice. Diabetologia. 2010; 53:1927-1934.
31. Tan C, Voss U, Svensson S, Erlinge D and Olde B. High
glucose and free fatty acids induce beta cell apoptosis
autocrine effects of ADP acting on the P2Y(13) receptor.
Purinergic Signal. 2013; 9:67-79.
32. Gallego D, Gil V, Aleu J, Martinez-Cutillas M, Clave P and
Jimenez M. Pharmacological characterization of purinergic
inhibitory neuromuscular transmission in the human colon.
Neurogastroenterol Motil. 2011; 23:792-e338.
33. Gallego D, Malagelada C, Accarino A, De Giorgio
R, Malagelada JR, Azpiroz F and Jimenez M.
Nitrergic and purinergic mechanisms evoke inhibitory
neuromuscular transmission in the human small intestine.
Neurogastroenterology and Motility. 2014; 26:419-429.
34. Wang GD, Wang XY, Hu HZ, Liu S, Gao N, Fang X, Xia
Y and Wood JD. Inhibitory neuromuscular transmission
mediated by the P2Y1 purinergic receptor in guinea pig
small intestine. Am J Physiol Gastrointest Liver Physiol.
35. Grasa L, Gil V, Gallego D, Martin MT and Jimenez M.
P2Y(1) receptors mediate inhibitory neuromuscular
transmission in the rat colon. British Journal of
Pharmacology. 2009; 158:1641-1652.
36. Christo FL, Wunderlich J, Yu JG, Wang YZ, Xue JJ,
Guzman J, Javed N and Cooke H. Mechanically evoked
reex electrogenic chloride secretion in rat distal colon is
triggered by endogenous nucleotides acting at P2Y1, P2Y2,
and P2Y4 receptors. Journal of Comparative Neurology.
37. Ghanem E, Robaye B, Leal T, Leipziger J, Van Driessche
W, Beauwens R and Boeynaems JM. The role of epithelial
P2Y2 and P2Y4 receptors in the regulation of intestinal
chloride secretion. Br J Pharmacol. 2005; 146:364-369.
38. Dong X, Smoll EJ, Ko KH, Lee J, Chow JY, Kim HD,
Insel PA and Dong H. P2Y receptors mediate Ca2+
signaling in duodenocytes and contribute to duodenal
mucosal bicarbonate secretion. American Journal of
Physiology-Gastrointestinal and Liver Physiology. 2009;
39. Matos JE, Robaye B, Boeynaems JM, Beauwens R and
Leipziger J. K+ secretion activated by luminal P2Y2 and
P2Y4 receptors in mouse colon. J Physiol. 2005; 564:269-
40. Kottgen M, Lofer T, Jacobi C, Nitschke R, Pavenstadt H,
Schreiber R, Frische S, Nielsen S and Leipziger J. P2Y6
receptor mediates colonic NaCl secretion via differential
activation of cAMP-mediated transport. Journal of Clinical
Investigation. 2003; 111:371-379.
41. Gendaszewska-Darmach E and Kucharska M. Nucleotide
receptors as targets in the pharmacological enhancement of
dermal wound healing. Purinergic Signalling. 2011; 7:193-
42. Boyer JL, Durham T, Barnes M, Navratil T and Schaberg
A. Denufosol tetrasodium, a P2Y2 receptor agonist for the
treatment of Cystic Fibrosis. Purinergic Signalling. 2010;
43. Myrtek D and Idzko M. Chemotactic activity of
extracellular nucleotideson human immune cells. Purinergic
Signal. 2007; 3:5-11.
44. Ferrari D, la Sala A, Panther E, Norgauer J, Di Virgilio
F and Idzko M. Activation of human eosinophils via P2
receptors: novel ndings and future perspectives. Journal
of Leukocyte Biology. 2006; 79:7-15.
45. Knowles MR, Clarke LL and Boucher RC. Activation by
extracellular nucleotides of chloride secretion in the airway
epithelia of patients with cystic brosis. N Engl J Med.
46. Kunzli BM, Berberat PO, Giese T, Csizmadia E,
Kaczmarek E, Baker C, Halaceli I, Buchler MW, Friess H
and Robson SC. Upregulation of CD39/NTPDases and P2
receptors in human pancreatic disease. American Journal
of Physiology-Gastrointestinal and Liver Physiology. 2007;
47. Cicko S, Lucattelli M, Muller T, Lommatzsch M, De
Cunto G, Cardini S, Sundas W, Grimm M, Zeiser R, Durk
T, Zissel G, Boeynaems JM, Sorichter S, Ferrari D, Di
Virgilio F, Virchow JC, et al. Purinergic Receptor Inhibition
Prevents the Development of Smoke-Induced Lung Injury
and Emphysema. Journal of Immunology. 2010; 185:688-
48. Lommatzsch M, Cicko S, Muller T, Lucattelli M, Bratke K,
Stoll P, Grimm M, Durk T, Zissel G, Ferrari D, Di Virgilio
F, Sorichter S, Lungarella G, Virchow JC and Idzko
M. Extracellular Adenosine Triphosphate and Chronic
Obstructive Pulmonary Disease. American Journal of
Respiratory and Critical Care Medicine. 2010; 181:928-934.
49. Ayata CK, Ganal SC, Hockenjos B, Willim K, Vieira
RP, Grimm M, Robaye B, Boeynaems JM, Di Virgilio F,
Pellegatti P, Diefenbach A, Idzko M and Hasselblatt P.
Purinergic P2Y(2) receptors promote neutrophil inltration
and hepatocyte death in mice with acute liver injury.
Gastroenterology. 2012; 143:1620-1629 e1624.
50. Dranoff JA, Ogawa M, Kruglov EA, Gaca MD, Sevigny J,
Robson SC and Wells RG. Expression of P2Y nucleotide
receptors and ectonucleotidases in quiescent and activated
rat hepatic stellate cells. Am J Physiol Gastrointest Liver
Physiol. 2004; 287:G417-424.
51. Ishimaru M, Yusuke N, Tsukimoto M, Harada H,
Takenouchi T, Kitani H and Kojima S. Purinergic signaling
via P2Y receptors up-mediates IL-6 production by liver
macrophages/Kupffer cells. Journal of Toxicological
Sciences. 2014; 39:413-423.
52. Langlois C and Gendron FP. Promoting M Phi
transepithelial migration by stimulating the epithelial cell
P2Y(2) receptor. European Journal of Immunology. 2009;
53. Degagne E, Grbic DM, Dupuis AA, Lavoie EG, Langlois
C, Jain N, Weisman GA, Sevigny J and Gendron FP.
P2Y(2) Receptor Transcription Is Increased by NF-kappa
B and Stimulates Cyclooxygenase-2 Expression and
PGE(2) Released by Intestinal Epithelial Cells. Journal of
Immunology. 2009; 183:4521-4529.
54. Degagne E, Turgeon N, Moore-Gagne J, Asselin C and
Gendron FP. P2Y(2) receptor expression is regulated by C/
EBP beta during inammation in intestinal epithelial cells.
Febs Journal. 2012; 279:2957-2965.
55. Donnell AMO and Puri P. Deciency of purinergic P2Y
receptors in aganglionic intestine in Hirschsprung’s disease.
Pediatric Surgery International. 2008; 24:77-80.
56. Grbic D, Degagne E, Langlois C, Dupuis AA and Gendron
FP. Intestinal inammation increases P2Y6 receptor
expression on epithelial cells and the release of CXCL8 by
UDP. Purinergic Signalling. 2008; 4:S184-S184.
57. Grbic DM, Degagne E, Larrivee JF, Bilodeau MS,
Vinette V, Arguin G, Stankova J and Gendron FP. P2Y6
receptor contributes to neutrophil recruitment to inamed
intestinal mucosa by increasing CXC chemokine ligand 8
expression in an AP-1-dependent manner in epithelial cells.
Inammatory Bowel Diseases. 2012; 18:1456-1469.
58. Somers GR, Hammet FM, Trute L, Southey MC and Venter
DJ. Expression of the P2Y6 purinergic receptor in human
T cells inltrating inammatory bowel disease. Lab Invest.
59. White N, Ryten M, Clayton E, Butler P and Burnstock G.
P2Y purinergic receptors regulate the growth of human
melanomas. Cancer Letters. 2005; 224:81-91.
60. Greig AVH, Linge C, Healy V, Lim P, Clayton E, Rustin
MHA, McGrouther DA and Burnstock G. Expression of
purinergic receptors in non-melanoma skin cancers and
their functional roles in A431 cells. Journal of Investigative
Dermatology. 2003; 121:315-327.
61. Song S, Jacobson KN, McDermott KM, Reddy SP, Cress
AE, Tang H, Dudek SM, Black SM, Garcia JG, Makino A
and Yuan JX. ATP Promotes Cell Survival Via Regulation
of Cytosolic [Ca2+] and Bcl-2/Bax Ratio in Lung Cancer
Cells. Am J Physiol Cell Physiol. 2015:ajpcell 00092
62. Schafer R, Sedehizade F, Welte T and Reiser G. ATP-
and UTP-activated P2Y receptors differently regulate
proliferation of human lung epithelial tumor cells. American
Journal of Physiology-Lung Cellular and Molecular
Physiology. 2003; 285:L376-L385.
63. Li WH, Qiu Y, Zhang HQ, Liu Y, You JF, Tian XX and
Fang WG. P2Y2 receptor promotes cell invasion and
metastasis in prostate cancer cells. British Journal of
Cancer. 2013; 109:1666-1675.
64. Li WH, Qiu Y, Zhang HQ, Tian XX and Fang WG. P2Y2
Receptor and EGFR Cooperate to Promote Prostate Cancer
Cell Invasion via ERK1/2 Pathway. Plos One. 2015; 10.
65. Chen L, He HY, Li HM, Zheng J, Heng WJ, You JF and
Fang WG. ERK1/2 and p38 pathways are required for P2Y
receptor-mediated prostate cancer invasion. Cancer Letters.
66. Wei Q, Costanzi S, Liu QZ, Gao ZG and Jacobson KA.
Activation of the P2Y1 receptor induces apoptosis and
inhibits proliferation of prostate cancer cells. Biochem
Pharmacol. 2011; 82:418-425.
67. Tu MT, Luo SF, Wang CC, Chien CS, Chiu CT, Lin CC
and Yang CM. P2Y(2) receptor-mediated proliferation of
C(6) glioma cells via activation of Ras/Raf/MEK/MAPK
pathway. Br J Pharmacol. 2000; 129:1481-1489.
68. Wypych D and Pomorski P. P2Y1 nucleotide receptor
silencing and its effect on glioma C6 calcium signaling.
Acta Biochim Pol. 2012; 59:711-717.
69. Joo YN, Jin H, Eun SY, Park SW, Chang KC and Kim
HJ. P2Y(2)R activation by nucleotides released from
the highly metastatic breast cancer cell contributes
to pre-metastatic niche formation by mediating lysyl
oxidase secretion, collagen crosslinking, and monocyte
recruitment. Oncotarget. 2014; 5:9322-9334. doi: 10.18632/
70. Li HJ, Wang LY, Qu HN, Yu LH, Burnstock G, Ni X,
Xu MJ and Ma B. P2Y(2) receptor-mediated modulation
of estrogen-induced proliferation of breast cancer cells.
Molecular and Cellular Endocrinology. 2011; 338:28-37.
71. Jin H, Eun SY, Lee JS, Park SW, Lee JH, Chang KC and
Kim HJ. P2Y(2) receptor activation by nucleotides released
from highly metastatic breast cancer cells increases tumor
growth and invasion via crosstalk with endothelial cells.
Breast Cancer Research. 2014; 16.
72. Eun SY, Ko YS, Park SW, Chang KC and Kim HJ. P2Y(2)
nucleotide receptor-mediated extracellular signal-regulated
kinases and protein kinase C activation induces the invasion
of highly metastatic breast cancer cells. Oncology Reports.
73. Sarangi S, Pandey A, Papa AL, Sengupta P, Kopparam
J, Dadwal U, Basu S and Sengupta S. P2Y12 receptor
inhibition augments cytotoxic effects of cisplatin in breast
cancer. Medical Oncology. 2013; 30.
74. Kim HJ, Jin H, Chang KC, Park SW and Lee JH.
Nucleotides released from breast cancer cells MDA-
MB-231 increase proliferation and invasion through P2Y(2)
receptor activation. Febs Journal. 2012; 279:168-169.
75. Chadet S, Jelassi B, Wannous R, Angoulvant D, Chevalier
S, Besson P and Roger S. The activation of P2Y(2) receptors
increases MCF-7 breast cancer cells migration through the
MEK-ERK1/2 signalling pathway. Carcinogenesis. 2014;
76. Schultze-Mosgau A, Katzur AC, Arora KK, Stojilkovic SS,
Diedrich K and Ortmann O. Characterization of calcium-
mobilizing, purinergic P2Y(2) receptors in human ovarian
cancer cells. Mol Hum Reprod. 2000; 6:435-442.
77. Conigrave AD, van der Weyden L, Holt L, Jiang L, Wilson
P, Christopherson RI and Morris MB. Extracellular ATP-
dependent suppression of proliferation and induction of
differentiation of human HL-60 leukemia cells by distinct
mechanisms. Biochem Pharmacol. 2000; 60:1585-1591.
78. Maaser K, Hopfner M, Kap H, Sutter AP, Barthel B,
von Lampe B, Zeitz M and Scherubl H. Extracellular
nucleotides inhibit growth of human oesophageal cancer
cells via P2Y(2)-receptors. Br J Cancer. 2002; 86:636-644.
79. Junankar PR, Karjalainen A and Kirk K. The role of P2Y1
purinergic receptors and cytosolic Ca2+ in hypotonically
activated osmolyte efux from a rat hepatoma cell line. J
Biol Chem. 2002; 277:40324-40334.
80. Dolovcak S, Waldrop SL, Fitz JG and Kilic G. Copper
inhibits P2Y(2)-dependent Ca2+ signaling through the
effects on thapsigargin-sensitive Ca2+ stores in HTC
hepatoma cells. Biochemical and Biophysical Research
Communications. 2010; 397:493-498.
81. Espelt MV, Pinto FD, Alvarez CL, Alberti GS, Incicco J,
Denis MFL, Davio C and Schwarzbaum PJ. On the role of
ATP release, ectoATPase activity, and extracellular ADP in
the regulatory volume decrease of Huh-7 human hepatoma
cells. American Journal of Physiology-Cell Physiology.
82. Xie R, Xu J, Wen G, Jin H, Liu X, Yang Y, Ji B, Jiang
Y, Song P, Dong H and Tuo B. The P2Y2 nucleotide
receptor mediates the proliferation and migration of human
hepatocellular carcinoma cells induced by ATP. J Biol
Chem. 2014; 289:19137-19149.
83. Haddad PS, Vallerand D, Mathe L, Benzeroual K and Van
de Werve G. Synergistic activation of mitogen-activated
protein kinase by insulin and adenosine triphosphate in liver
cells: permissive role of Ca2+. Metabolism. 2003; 52:590-
84. Scho C, Ponczek M, Mader T, Waring M, Benecke H,
von zur Muhlen A, Mix H, Cornberg M, Boker KH, Manns
MP and Wagner S. Regulation of cytosolic free calcium
concentration by extracellular nucleotides in human
hepatocytes. Am J Physiol. 1999; 276:G164-172.
85. Elsing C, Georgiev T, Hubner CA, Boger R, Stremmel W
and Schlenker T. Extracellular ATP Induces Cytoplasmic
and Nuclear Ca2+ Transients
P2Y2 Receptor in Human
Biliary Epithelial Cancer Cells (Mz-Cha-1). Anticancer
Research. 2012; 32:3759-3767.
86. Ko T, An HJ, Ji YG, Kim OJ and Lee DH. P2Y Receptors
Regulate Proliferation of Human Pancreatic Duct Epithelial
Cells. Pancreas. 2012; 41:797-803.
87. Choi JH, Ji YG and Lee DH. Uridine triphosphate increases
proliferation of human cancerous pancreatic duct epithelial
cells by activating P2Y2 receptor. Pancreas. 2013; 42:680-
88. Verspohl EJ, Johannwille B, Waheed A and Neye H. Effect
of purinergic agonists and antagonists on insulin secretion
from INS-1 cells (insulinoma cell line) and rat pancreatic
islets. Can J Physiol Pharmacol. 2002; 80:562-568.
89. Nylund G, Hultman L, Nordgren S and Delbro DS. P2Y2-
and P2Y4 purinergic receptors are over-expressed in human
colon cancer. Auton Autacoid Pharmacol. 2007; 27:79-84.
90. Nylund G, Nordgren S and Delbro DS. Expression of P2Y2
purinoceptors in MCG 101 murine sarcoma cells, and HT-
29 human colon carcinoma cells. Auton Neurosci. 2004;
91. Hopfner M, Maaser K, Barthel B, von Lampe B, Hanski C,
Riecken EO, Zeitz M and Scherubl H. Growth inhibition
and apoptosis induced by P2Y2 receptors in human
colorectal carcinoma cells: involvement of intracellular
calcium and cyclic adenosine monophosphate. Int J
Colorectal Dis. 2001; 16:154-166.
92. White N and Burnstock G. P2 receptors and cancer. Trends
in Pharmacological Sciences. 2006; 27:211-217.
93. Hopfner M, Lemmer K, Jansen A, Hanski C, Riecken EO,
Gavish M, Mann B, Buhr H, Glassmeier G and Scherubl H.
Expression of functional P2-purinergic receptors in primary
cultures of human colorectal carcinoma cells. Biochem
Biophys Res Commun. 1998; 251:811-817.
94. Coutinho-Silva R, Stahl L, Cheung KK, de Campos NE,
de Oliveira Souza C, Ojcius DM and Burnstock G. P2X
and P2Y purinergic receptors on human intestinal epithelial
carcinoma cells: effects of extracellular nucleotides on
apoptosis and cell proliferation. Am J Physiol Gastrointest
Liver Physiol. 2005; 288:G1024-1035.
95. Limami Y, Pinon A, Leger DY, Pinault E, Delage C,
Beneytout JL, Simon A and Liagre B. The P2Y2/Src/p38/
COX-2 pathway is involved in the resistance to ursolic acid-
induced apoptosis in colorectal and prostate cancer cells.
Biochimie. 2012; 94:1754-1763.
96. Limami Y, Pinon A, Leger DY, Mousseau Y, Cook-Moreau
J, Beneytout JL, Delage C, Liagre B and Simon A. HT-29
colorectal cancer cells undergoing apoptosis overexpress
COX-2 to delay ursolic acid-induced cell death. Biochimie.
97. Buzzi N, Bilbao PS, Boland R and Boland AR. Extracellular
ATP activates MAP kinase cascades through a P2Y
purinergic receptor in the human intestinal Caco-2 cell line.
Biochimica Et Biophysica Acta-General Subjects. 2009;
98. Buzzi N, Boland R and de Boland AR. Signal transduction
pathways associated with ATP-induced proliferation of
colon adenocarcinoma cells. Biochimica Et Biophysica
Acta-General Subjects. 2010; 1800:946-955.
99. Yaguchi T, Saito M, Yasuda Y, Kanno T, Nakano T and
Nishizaki T. Higher concentrations of extracellular ATP
suppress proliferation of Caco-2 human colonic cancer cells
via an unknown receptor involving PKC inhibition. Cell
Physiol Biochem. 2010; 26:125-134.
100. Bahrami F, Kukulski F, Lecka J, Tremblay A, Pelletier
J, Rockenbach L and Sevigny J. Purine-Metabolizing
Ectoenzymes Control IL-8 Production in Human Colon HT-
29 Cells. Mediators of Inammation. 2014; 2014:879895.