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Abstract
Abstract Transforming growth factor-beta (TGF-β) plays an important role in the progression of prostate cancer. It exhibits both tumor suppressor and tumor promoting activities. Correlations between COX-2 overexpression and enhanced production of PGE2 have been implicated in cancer progression; however, there are no studies indicating that TGF-β effects in prostate cancer cells involve PGE2 synthesis. In this study, we investigated TGF-β regulation of COX-1 and COX-2 expression in prostate cancer cells and whether the effects of TGF-β on cell proliferation and migration are mediated by PGE2. COX-1 protein was ubiquitously expressed in prostate cells; however, COX-2 protein levels were only detected in prostate cancer cells. TGF-β treatment increased COX-2 protein levels and PGE2 secretion in PC3 cells. Exogenous PGE2 and PGF2α had no effects on cell proliferation in LNCaP, DU145, and PC3 cells while PGE2 and TGF-β induced migratory behavior only in PC3 cells. Only EP2 and EP4 receptors were detected at mRNA levels in prostate cells. The EP4-targeting siRNA inhibited PGE2 and TGF-β-induced migration of PC3 cells. PGE2 and TGF-β induced phosphorylation of AKT which was blocked by antagonists of PGE2 (EP4) receptors (L161982, AH23848) and PI3-kinase inhibitor (LY294002) in PC3 cells. Pretreatment with L161982 or AH23848 blocked the stimulatory effects of PGE2 and TGF-β on cell migration, while LY294002 or rapamycin completely eliminated PGE2, TGF-β, and EGF-induced migration PC3 cells. We conclude that TGF-β increases COX-2 levels and PGE2 secretion in prostate cancer cells which, in turn, mediates TGF-β effects on cell migration through the activation of PI3K/AKT/mTOR pathway. Acknowledgements: These studies were supported by the NIH/NIMHD/RCMI grant #G12MD007590, NIH/NIMHD #5P20MD002285, and DOD grant # W8I-08-1-0077. Citation Format: Baohan T. Vo, Derrick Morton, Shravan Komaragiri, Ana C. Millena, Shafiq A. Khan. TGF-β Effects on prostate cancer cell migration are mediated by PGE2 through activation of PI3K/AKT/mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4080. doi:10.1158/1538-7445.AM2013-4080
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