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

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

doi: 10.1097/MPA.0000000000001055
Original Articles

Objectives The aim of this study was to investigate the effects of the activated P2X7 receptors on the proliferation and growth of human pancreatic cancer cells.

Methods Proliferation was measured by incorporating bromodeoxyuridine into pancreatic cancer cells, MIA PaCa-2 and HPAC. Expression of P2 receptors and signal molecules was examined using quantitative reverse transcription/polymerase chain reaction and/or Western blot. Proliferative effects of the P2X7 receptors in vivo were examined using a xenotransplant model of pancreatic cancer cell lines.

Results Incubating pancreatic cancer cells with adenosine triphosphate (ATP) and 2′(3′)-O-(4-Benzoylbenzoyl)ATP resulted in a dose-dependent increase of cell proliferation. The P2 receptor antagonist, KN-62, and small interfering RNA against P2X7 receptors, significantly decreased the proliferative effects of ATP. The ATP-induced proliferation was mediated by protein kinase C, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK); specifically, ATP increased the phosphorylation of ERK1/2 and JNK. The expression of inducible nitric oxide synthase was decreased by P2X7 receptor activation. In a xenotransplant model, applying ATP significantly increased the growth of induced tumors.

Conclusions 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.

From the *Departments of Physiology and †Preventive Medicine, School of Medicine, and ‡College of Life Science, CHA University, Seongnam, Gyeonggi, Republic of Korea.

Received for publication May 20, 2017; accepted March 2, 2018.

Address correspondence to: Dong Hyeon Lee, MD, PhD, Department of Physiology, School of Medicine, CHA University, 713, CHA BIO Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463–400 Republic of Korea (e-mail: leedh@cha.ac.kr).

This study was supported by Priority Research Centers Program and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2009-0093821 and NRF-2017R1D1A1B03035616).

The authors declare no conflict of interest.

JH Choi and YG Ji contributed equally to this work.

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