TGF-β effects on prostate cancer cell migration and invasion are mediated by PGE(2) through activation of PI3K/AKT/mTOR pathway - Abstract

TGF-β plays an important role in the progression of prostate cancer.

It exhibits both tumor suppressor and tumor-promoting activities. Correlations between cyclooxygenase (COX)-2 overexpression and enhanced production of prostaglandin (PG)E₂ 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 detected only in prostate cancer cells. TGF-β treatment increased COX-2 protein levels and PGE₂ secretion in PC3 cells. Exogenous PGE₂ and PGF_2α had no effects on cell proliferation in LNCaP, DU145, and PC3 cells whereas PGE₂ and TGF-β induced migration and invasive behavior in PC3 cells. Only EP2 and EP4 receptors were detected at mRNA levels in prostate cells. The EP4-targeting small interfering RNA inhibited PGE₂ and TGF-β-induced migration of PC3 cells. TGF-β and PGE₂ induce activation of PI3K/AKT/mammalian target of rapamycin pathway as indicated by increased AKT, p70S6K, and S6 phosphorylation. Rapamycin completely blocked the effects of TGF-β and PGE₂ on phosphorylation of p70S6K and S6 but not on AKT phosphorylation. PGE₂ and TGF-β induced phosphorylation of AKT, which was blocked by antagonists of PGE₂ (EP4) receptors (L161982, AH23848) and PI3K inhibitor (LY294002) in PC3 cells. Pretreatment with L161982 or AH23848 blocked the stimulatory effects of PGE₂ and TGF-β on cell migration, whereas LY294002 or rapamycin completely eliminated PGE₂, TGF-β, and epidermal growth factor-induced migration in PC3 cells. We conclude that TGF-β increases COX-2 levels and PGE₂ secretion in prostate cancer cells which, in turn, mediate TGF-β effects on cell migration and invasion through the activation of PI3K/AKT/mammalian target of rapamycin pathway.

Written by:
Vo BT, Morton D Jr, Komaragiri S, Millena AC, Leath C, Khan SA.   Are you the author?
Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Drive, SW, Atlanta, Georgia 30314.

Reference: Endocrinology. 2013 May;154(5):1768-79.
doi: 10.1210/en.2012-2074

PubMed Abstract
PMID: 23515290

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