TGF-β Effects on Prostate Cancer Cell Migration and Invasion Are Mediated by PGE2 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 PGF2α 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.

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

“…Here, our results suggested that the AKT/mTOR signaling pathway was involved in the autophagy activation by PGE1 treatment under HG. It was reported that PGE2 induced the activation of the PI3K/AKT/ mTOR pathway in prostate cancer cells or mast cell chemotaxis [17]. Based on our results, it was suggested that AKT/mTOR signal pathway was responsible for the regulation of PGE1 on autophagy.…”

MicroRNA-214 acts as a potential oncogene in breast cancer by targeting the PTEN-PI3K/Akt signaling pathway

“…The abnormal activation of this pathway has been corroborated by epidemiological and experimental studies as a critical step toward the initiation and maintenance of human tumors. Previous research has demonstrated that PI3K/Akt triggers a cascade of multiple signals that regulate cancer cell proliferation, invasion, metastasis, survival as well as affecting prognosis (24,25). Thus, in this study, to explore the mechanisms involved in the miR-214-mediated increase in cell viability and resistance to apoptosis, we examined the involvement of PI3K/Akt signaling in these processes.…”

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

“…Based on these findings, the PI 3 K/Akt/mTOR pathway is believed to be a promising therapeutic target for the treatment of cancer, and small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity [43,44]. For example, TGF-β increased COX-2 levels and PGE 2 secretion in prostate cancer cells which, in turn, mediate TGF-β effects on cell migration and invasion through the activation of PI 3 K/AKT/mTOR pathway [45]. Thioridazine, a well-known anti-psychotic agent was found to induce apoptosis by targeting the PI 3 K/Akt/mTOR pathway in cervical and endometrial cancer cells [46].…”