Abstract 1081: Expression of TGFβ3 and its effects on migratory and invasive behavior in prostate cancer cells: Involvement of PI3K/Akt pathway

Abstract

Abstract Transforming Growth Factor-β (TGFβ) is a secreted protein that is involved in the regulation of many cellular processes and has been implicated as a factor in cancer cell invasion and metastasis. Studies have indicated that different TGFβ isoforms may exert differential effects on cancer cells during different stages of the disease, however very little is known about the expression patterns of the 3 isoforms in prostate cancer. Non-traditional signaling pathways including PI3-kinase have been associated with TGFβ-mediated effects on cancer cell invasion and metastasis. Whether or not TGFβ isoforms play a differential role in migration and invasion of prostate cancer, and act through PI3-Kinase, has not been investigated. 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 cancers and studied the differential effects of specific isoforms on migratory, invasive behavior and induction of the PI3-Kinase and MAPK/ERK pathways. TGFβ1 and TGF-β3 were expressed in all cell lines, with TGFβ3 increasing in metastatic cell lines. TGFβ1 and TGFβ3 induced motility and invasive behavior in PC3 cells, with TGFβ3 being more potent in inducing invasive behavior. TGF-β3 caused a significant increase in the phosphorylation of AKT (pAKT), a downstream target of PI3-Kinase, in PC3 cells. LY294002, a PI3-kinase inhibitor, blocked this induced migration and phosphorylation of AKT. Inhibitors of TGFβRI (SB431524) and Smad-3 (SIS3) blocked TGF-β induced motility and TGFβ isoform induced pAKT. There was no differential isoform effect on the phosphorylation of ERK (pERK). PD98059, a MAPK/ERK inhibitor, did inhibit any TGFβ induced migration and pERK, but did not affect isoform induced pAKT. Furthermore, TGFβ isoforms may be differentially phosphorylating Smad-2 and Smad-3 in PC3 cells. 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 mediated via the PI3-Kinase pathway and are TGFβRI and Smad-3 dependent. Grant support: MBRS-RISE 2R25GM060414, NIH 1P20MD002285-02 and RCMI G12RR03602 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1081. doi:1538-7445.AM2012-1081