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

• Published in: Carcinogenesis (New York) 2009-03, Vol.30 (3), p.457-465
• Main Authors: Komachi, Mayumi, Tomura, Hideaki, Malchinkhuu, Enkhzol, Tobo, Masayuki, Mogi, Chihiro, Yamada, Takayuki, Kimura, Takao, Kuwabara, Atsushi, Ohta, Hideo, Im, Doon-Soon, Kurose, Hitoshi, Takeyoshi, Izumi, Sato, Koichi, Okajima, Fumikazu
• Format: Article
• Language: English
• Subjects: Ascites - metabolism; Ascites - pathology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Cell Movement - drug effects; Collagen; Drug Combinations; Epidermal Growth Factor - pharmacology; Gastroenterology. Liver. Pancreas. Abdomen; GTP-Binding Protein alpha Subunits, Gi-Go - antagonists & inhibitors; Humans; Isoxazoles - pharmacology; Laminin; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lysophospholipids - pharmacology; Medical sciences; Neoplasm Invasiveness; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pertussis Toxin - pharmacology; Propionates - pharmacology; Proteoglycans; Receptors, Lysophosphatidic Acid - agonists; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - physiology; rhoA GTP-Binding Protein - metabolism; RNA, Small Interfering - genetics; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgp011

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.