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.