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.
Transforming growth factor-β (TGFβ) is a secreted cytokine implicated as a factor in cancer cell migration and invasion. Previous studies have indicated that TGFβ isoforms may exert differential effects on cancer cells during different stages of the disease, however very little is known about the expression patterns and activity of the three isoforms in prostate cancer. Non-traditional signaling pathways including the PI3-Kinase have been associated with TGFβ-mediated effects on cancer cell invasion. In the present study, we have carried out expression analysis of TGFβ isoforms and signaling components in cell line models representing different stages of prostate cancer and studied the differential effects of specific isoforms on migratory and invasive behavior and induction of the PI3-kinase pathway. TGFβ1 and TGFβ3 were expressed in all cell lines, with TGFβ3 expression increasing in metastatic cell lines. Both TGFβ1 and TGFβ3 induced motility and invasive behavior in PC3 cells, however, TGFβ3 was significantly more potent than TGFβ1. TGFβRI and Smad3 inhibitors blocked TGFβ1 and TGFβ3 induced motility and invasion. TGFβ3 caused a significant increase in pAKTser473 in PC3 cells and PI3-kinase inhibitor LY294002 blocked TGFβ3 induced migration, invasion and phosphorylation of AKT. Both TGFβRI and Smad3 inhibitors blocked TGFβ3 induced pAKTser473. Based on these results, we conclude that TGFβ3 is expressed in metastatic prostate cancer cell lines and is involved in induction of invasive behavior in these cells. Furthermore, these effects of TGFβ3 are TGFβRI and Smad3 dependent and mediated via the PI3-kinase pathway.
Expression of genes that encode oxytocin (OXT) and vasopressin (AVP) and their cognate receptors in normal and diseased prostates are only partially characterized. Reverse transcription and PCR were used to examine the expression of these genes in normal prostate epithelial and stromal cell lines, k-ras-transformed prostate epithelial cell lines, and in four prostate cancer cell lines. Secreted and cell-associated OXT peptide was measured by an enzyme immunoassay. OXT and its receptor (OXTR) were expressed in all eight prostate cell lines. Cellassociated OXT peptide was also found in all prostate epithelial cell lines except in DU145 cells. Neither AVP nor its cognate receptors (V1a receptor and V2 receptor) were expressed in any prostate cell line examined. These data point to the OXTR as the primary target of OXT and AVP, and suggest that OXT might be an autocrine/paracrine regulator in human prostate. We found that OXT induces the migration of PC3 and PC3M, but not DU145 prostate cancer cells. The effect of OXT is distinct from the epidermal growth factor (EGF)-induced migration of prostate cancer cells, in which ERK1/2 and EGF receptor kinase activities were required. When cells were pretreated with pertussis toxin, the effect of OXT, but not EGF, on cell migration was abolished. Pretreatment with the cyclic AMP analogue, 8-Br-cAMP, did not affect OXT-induced cell migration, which eliminated the nonspecific effect of pertussis toxin. We conclude that a Gi-dependent mechanism is involved in OXTR-mediated migration of prostate cancer cells, and indicates a role for OXTR in prostate cancer metastasis. Mol Cancer Res; 8(8); 1164-72. ©2010 AACR.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.