Prostate cancer remains the most frequently diagnosed
malignancy and the second leading cause of
cancer mortality among men in the United States.
Hormone refractory, metastatic disease has no molecular
therapeutics to date and survival is poor.
Lysophosphatidic acid (LPA) is a bioactive
lipid exhibiting motility, invasive, growth, proliferative and survival effects in multiple
cancer cell lineages. Cells express different combinations of LPA-specific
G protein-coupled receptors, LPA(1), LPA(2) LPA(3), and LPA(4) as well as other
LPA receptors, which bind LPA and thereby regulate
lipid signaling. The role of specific
LPA receptors in functional outcomes of lysolipid signaling remains to be fully elucidated in
prostate cancer. We hypothesized that LPA can initiate cell migration through specific
LPA receptors by activating actin-associating
proteins involved in motility, including the
vasodilator-stimulated phosphoprotein (VASP). In the present study, we demonstrate that LPA-induced lamellipodia formation in cells is dependent on
LPA receptor-mediated phosphorylation of VASP, demonstrating a previously unknown regulation by LPA. LPA induces phosphorylation of VASP at Ser(157), through
protein kinase A (PKA) since the stimulation was abrogated by PKA inhibition. In addition, we found the effects of LPA-induced lamellipodia formation and migration were reduced by knockdown of either VASP or
LPA receptor expression, suggesting that
LPA receptor-induced VASP phosphorylation is a critical mediator of migration initiation. Thus the LPA(2) and LPA(3) receptors, in addition to the previously implicated
LPA(1) receptor, play a role in cellular motility potentially contributing to invasion and
metastases. Emerging drugs targeting the LPA pathway may be beneficial for the treatment of metastatic progression in
prostate cancer.