LPA1 receptors mediate stimulation, whereas LPA2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites.
Malignant ascites from pancreatic cancer patients has been reported to stimulate migration of pancreatic cancer cells through lysophosphatidic acid (LPA) and LPA(1) receptors. Indeed, ascites- and LPA-induced migration was inhibited by Ki16425, an LPA(1) and LPA(3) 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 G(i) protein inhibitor, and attenuated by a small interfering RNA (siRNA) specific to the LPA(2) 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 LPA(2) receptor. Moreover, LP-105, an LPA(2) agonist, also inhibited EGF-induced migration in the PTX-treated cells. A similar inhibitory migration response through LPA(2) 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 LPA(2) receptors are coupled to the G(12/13) protein/Rho-signaling pathway, leading to the inhibition of EGF-induced migration and invasion of pancreatic cancer cells.
Komachi
Mayumi
M
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
Tomura
Hideaki
H
Malchinkhuu
Enkhzol
E
Tobo
Masayuki
M
Mogi
Chihiro
C
Yamada
Takayuki
T
Kimura
Takao
T
Kuwabara
Atsushi
A
Ohta
Hideo
H
Im
Doon-Soon
DS
Kurose
Hitoshi
H
Takeyoshi
Izumi
I
Sato
Koichi
K
Okajima
Fumikazu
F
D001201:Ascites / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007797:Laminin; D008246:Lysophospholipids / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D037342:Pertussis Toxin / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011509:Proteoglycans; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D004338:Drug Combinations; D007555:Isoxazoles; D007797:Laminin; D008246:Lysophospholipids; D011422:Propionates; D011509:Proteoglycans; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; C059485:matrigel; D004815:Epidermal Growth Factor; D003094:Collagen; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid