Activating P2X7 Receptors Increases Proliferation of Human Pancreatic Cancer Cells via ERK1/2 and JNK

Choi, Ji Hun; Ji, Young Geon; Ko, Jung Jae; Cho, Han Jun; Lee, Dong Hyeon

doi:10.1097/mpa.0000000000001055

Cited by 42 publications

(30 citation statements)

References 36 publications

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“…Second, the P2X7R is a Ca 2+ channel promoting trophic effects on cell proliferation, cell metabolism, migration, invasion and cellular crosstalk. Therefore, it can also be considered pro-tumorigenic and probably occurs at lower concentrations of eATP (probably activating heteromeric P2X7A-P2X7B) [96,[99][100][101][102][103][104]. Third, P2X7R is expressed in tumor immune cells, and it can have both anti-and pro-tumorigenic effects [1,4,97,105,106].…”

Section: P2x7 Receptorsmentioning

confidence: 99%

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

Novak¹,

Yu²,

Magni³

et al. 2020

IJMS

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The purinergic signaling has an important role in regulating pancreatic exocrine secretion. The exocrine pancreas is also a site of one of the most serious cancer forms, the pancreatic ductal adenocarcinoma (PDAC). Here, we explore how the network of purinergic and adenosine receptors, as well as ecto-nucleotidases regulate normal pancreatic cells and various cells within the pancreatic tumor microenvironment. In particular, we focus on the P2X7 receptor, P2Y2 and P2Y12 receptors, as well as A2 receptors and ecto-nucleotidases CD39 and CD73. Recent studies indicate that targeting one or more of these candidates could present new therapeutic approaches to treat pancreatic cancer. In pancreatic cancer, as much as possible of normal pancreatic function should be preserved, and therefore physiology of purinergic signaling in pancreas needs to be considered.

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Section: P2x7 Receptorsmentioning

confidence: 99%

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

Novak¹,

Yu²,

Magni³

et al. 2020

IJMS

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“…Different types of ionotropic receptors including P2XR and NMDAR have been reported to be expressed in PDAC (Kunzli et al, 2007;Hansen et al, 2008;Burnstock and Novak, 2012;Li and Hanahan, 2013;North et al, 2017). Among P2XR, P2X7R is the most well described (Kunzli et al, 2007;Hansen et al, 2008;Burnstock and Novak, 2012).This ionotropic receptor has shown to be overexpressed in PDAC cell lines and tissue (Kunzli et al, 2007;Giannuzzo et al, 2015), and to be implicated in the proliferating, apoptotic, migrating, and invading processes of PDAC (Kunzli et al, 2007;Hansen et al, 2008;Giannuzzo et al, 2015;Giannuzzo et al, 2016;Choi et al, 2018). In addition, the expression of NMDAR was found in both PDAC cell lines and PDAC tumors, and their inhibition and blocking resulted in reduced different PDAC cell lines viability and survival (Li and Hanahan, 2013;North et al, 2017).…”

Section: Ionotropic Receptors In Pdac Purinergic Receptors (P2xr) Andmentioning

confidence: 99%

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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“…The target messenger RNA (mRNA) was knocked down using small interfering RNA (siRNA) as previously described. 6 21 Briefly, the siRNAs (Bioneer, Daejeon, Korea) against human SRC, AKT1, AKT2, and AKT3 were used. Cells were grown at 70% to 80% confluence overnight, followed by transfection with predesigned siRNA (50 nM) using Lipofectamine RNAiMAX transfection reagent as instructed by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…The xenotransplant model of pancreatic cancer was developed as previously described. 21 This study was approved and conducted in accordance with the regulations and guidelines of the Institutional Animal Care and Use Committee at CHA University (Seongnam, Korea). BALB/c nude mice were housed in a light- and temperature-controlled aseptic environment at the Laboratory Animal Research Center in CHA University.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Anti-Cancer Effects of AKT and SRC Inhibition in Human Pancreatic Cancer Cells

Ahn

et al. 2018

Yonsei Med J

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PurposeTo investigate the effect of combined inhibition of protein kinase B (AKT) and SRC on the growth and metastatic potential of human pancreatic cancer cells.Materials and MethodsAKT and SRC were inhibited using 10-DEBC and PP2, respectively. The expression of their messenger RNAs were down-regulated by specific small interfering RNA (siRNA). Changes in pancreatic cancer cell growth and metastatic potential were determined using a cell viability assay and a xenotransplant model of pancreatic cancer, as well as cell migration and invasion assays. Signal proteins were analyzed by Western blot.ResultsThe inhibitors 10-DEBC and PP2 suppressed cell proliferation in a dose-dependent fashion in pancreatic cancer cell lines MIA PaCa-2 and PANC-1. The simultaneous inhibition of AKT and SRC at low concentrations resulted in a significant suppression of cell proliferation. Knockdown of AKT2 and SRC using siRNAs also significantly decreased cell proliferation. In a pancreatic cancer model, combined treatment with 10-DEBC and PP2 also significantly suppressed the growth of pancreatic cancer. Application of 10-DEBC with PP2 significantly reduced the metastatic potential of pancreatic cancer cells by inhibiting migration and invasion. The combined inhibition suppressed the phosphorylation of mTOR and ERK in pancreatic cancer cells.ConclusionCombined targeting of AKT and SRC resulted in a synergistic efficacy against human pancreatic cancer growth and metastasis.

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Activating P2X7 Receptors Increases Proliferation of Human Pancreatic Cancer Cells via ERK1/2 and JNK

Abstract: The P2X7 receptor activation by extracellular nucleotides increased proliferation and growth of human pancreatic cancer cells via ERK1/2 and JNK. This supports the pathophysiological role of P2X7 receptors in pancreatic disease and recovery.

Cited by 42 publications

References 36 publications

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

Purinergic Signaling in Pancreas—From Physiology to Therapeutic Strategies in Pancreatic Cancer

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Synergistic Anti-Cancer Effects of AKT and SRC Inhibition in Human Pancreatic Cancer Cells

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