LPA-induced migration of ovarian cancer cells requires activation of ERM proteins via LPA 1 and LPA 2 .

Lysophosphatidic acid (LPA) has been implicated in the pathology of human ovarian cancer. This phospholipid elicits a wide range of cancer cell responses, such as proliferation, trans-differentiation, migration, and invasion, via various G-protein-coupled LPA receptors (LPARs). Here, we explored the cellular signaling pathway via which LPA induces migration of ovarian cancer cells. LPA induced robust phosphorylation of ezrin/radixin/moesin (ERM) proteins, which are membrane-cytoskeleton linkers, in the ovarian cancer cell line OVCAR-3. Among the LPAR subtypes expressed in these cells, LPA ₁ and LPA ₂ , but not LPA ₃ , induced phosphorylation of ERM proteins at their C-termini. This phosphorylation was dependent on the Gα _12/13 /RhoA pathway, but not on the Gα _q /Ca ²⁺ /PKC or Gα _s /adenylate cyclase/PKA pathway. The activated ERM proteins mediated cytoskeletal reorganization and formation of membrane protrusions in OVCAR-3 cells. Importantly, LPA-induced migration of OVCAR-3 cells was completely abolished not only by gene silencing of LPA ₁ or LPA ₂ , but also by overexpression of a dominant negative ezrin mutant (ezrin-T567A). Taken together, this study demonstrates that the LPA ₁ /LPA ₂ /ERM pathway mediates LPA-induced migration of ovarian cancer cells. These findings may provide a potential therapeutic target to prevent metastatic progression of ovarian cancer.
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