Prostaglandin F2α-induced TGFβ-PMEPA1 pathway is a critical mediator of epithelial plasticity and ovarian carcinoma progression

ABSTRACT Prostaglandin (PG) F 2α has been scarcely studied in cancer. We have identified a new role for PGF 2α in ovarian cancer, stimulating the production of TGFβ and the consequent induction of PMEPA1. We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated to higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival. Significance This work identifies Prostaglandin F 2α as an inducer, through NFAT, of TGFβ and together with this up-regulate PMEPA1, which is identified both as a drug target and as a prognostic biomarker in ovarian tumors, potentially useful in clinical practice.