Lysophosphatidic acid (LPA)-induced vasodilator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells

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Abstract

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, LPA1, LPA2 LPA3, and LPA4 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 that 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 LPA2 and LPA3 receptors, in addition to the previously implicated LPA1 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.

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