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Carcinogenesis Advance Access originally published online on January 7, 2009
Carcinogenesis 2009 30(3):457-465; doi:10.1093/carcin/bgp011
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites

Mayumi Komachi, Hideaki Tomura, Enkhzol Malchinkhuu, Masayuki Tobo, Chihiro Mogi, Takayuki Yamada, Takao Kimura1, Atsushi Kuwabara1, Hideo Ohta2, Doon-Soon Im3, Hitoshi Kurose4, Izumi Takeyoshi5, Koichi Sato and Fumikazu Okajima*

Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
1 Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan
2 Research Laboratory, Kirin Brewery Co., Ltd, 3 Miyahara, Takasaki 370-1295, Japan
3 Laboratory of Pharmacology, College of Pharmacy, Pusan National University, Busan, Republic of Korea 609-735
4 Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
5 Division of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan

* To whom correspondence should be addressed. Tel: +81 27 220 8850; Fax: +81 27 220 8895; Email: fokajima{at}showa.gunma-u.ac.jp

Correspondence may also be addressed to Hideaki Tomura. Tel: +81 27 220 8850; Fax: +81 27 220 8895; Email: tomurah{at}showa.gunma-u.ac.jp

Malignant ascites from pancreatic cancer patients has been reported to stimulate migration of pancreatic cancer cells through lysophosphatidic acid (LPA) and LPA1 receptors. Indeed, ascites- and LPA-induced migration was inhibited by Ki16425, an LPA1 and LPA3 antagonist, in Panc-1 cells. Unexpectedly, however, in the presence of Ki16425, ascites and LPA inhibited cell migration in response to epidermal growth factor (EGF). The inhibitory migratory response to ascites and LPA was also observed in the cells treated with pertussis toxin (PTX), a Gi protein inhibitor, and attenuated by a small interfering RNA (siRNA) specific to the LPA2 receptor. The inhibitory LPA action was reversed by the regulators of G-protein signaling domain of p115RhoGEF, dominant-negative RhoA or C3 toxin. Indeed, LPA activated RhoA, which was attenuated by the siRNA against the LPA2 receptor. Moreover, LP-105, an LPA2 agonist, also inhibited EGF-induced migration in the PTX-treated cells. A similar inhibitory migration response through LPA2 receptors was also observed in YAPC-PD, BxPC-3, CFPAC-1 and PK-1 pancreatic cancer cell lines. LPA also inhibited the invasion of Panc-1 cells in the PTX-treated cells in the in vitro Matrigel invasion assay. We conclude that LPA2 receptors are coupled to the G12/13 protein/Rho-signaling pathway, leading to the inhibition of EGF-induced migration and invasion of pancreatic cancer cells.

Abbreviations: BSA, bovine serum albumin; CHO, Chinese hamster ovary; EGF, epidermal growth factor; LPA, lysophosphatidic acid; MG lipase, monoglyceride lipase; mRNA, messenger RNA; MTT, 3-(4,5-dimethythiazol-2-yl)-diphenyltetrazolium bromide; PTX, pertussis toxin; RGS, regulators of G-protein signaling; siRNA, small interfering RNA; S1P, sphingosine 1-phosphate

Received September 8, 2008; revised December 15, 2008; accepted December 29, 2008.


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