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Carcinogenesis Advance Access published online on January 7, 2009
Carcinogenesis, 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 Komachi1, Hideaki Tomura1, Enkhzol Malchinkhuu1, Masayuki Tobo1, Chihiro Mogi1, Takayuki Yamada1, Takao Kimura1,2, Atsushi Kuwabara1,2, Hideo Ohta3, Doon-Soon Im4, Hitoshi Kurose5, Izumi Takeyoshi6, Koichi Sato1 and Fumikazu Okajima1,*

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

* To whom correspondence should be addressed. Tel.: +81-27-220-8850; Fax.: +81-27-220-8895; E-mail.: 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; E-mail.: 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 RGS 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.

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


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