Abstract 1107: Transforming growth factor-beta (TGF-β) increases Par-4 expression via activation of Smad and NF-κB in endometrial cancer cells

Abstract

Abstract Prostate apoptosis response-4 (Par-4) gene was originally identified in prostate cancer cells undergoing apoptosis. Further studies have shown that Par-4 selectively induces apoptosis in cancer cells without effecting normal cells. Recently it has been evidenced that Par-4 has a tumor suppressor role in endometrial cancer. We have previously demonstrated that TGF-β isoforms are expressed in endometrial tumors and determined cellular fate by regulating apoptosis through the activation of NF-κB. In the present study, we have investigated the mechanisms through which TGF-β isoforms regulate Par-4 expression in endometrial cancer cells. KLE and Hec-1-A endometrial cancer cell lines were used as model in this study. Transcript and protein levels were assessed by reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting, respectively. The results revealed that both cell lines express TGF-β receptor I and receptor II. Blocking TGF-β signalling by neutralizing TGF-β antibody reduced endogenous Par-4 mRNA and protein levels. Exogenous treatment with all the TGF-β isoforms (10ng/ml) upregulated Par-4 mRNA and protein levels. Furthermore, there was increase in the levels of phosphorylated Smad2 and Smad3 in response to TGF-β treatment, thus indicating that Smad pathway was activated by TGF-β isoforms in these cells. However, there was no change in the protein levels of total Smad2/3. TGF-β treatment resulted in rapid phosphorylation of IκB-α with no effect on total IκB-α levels thus suggesting an activation, nuclear translocation and increase in transcriptional activity of NF-κB. Collectively, these results suggest that each TGF-β isoform induces Par-4 levels via the activation of Smad and NF-κB pathway in endometrial cancer cells. Since downregulation of Par-4 is a common event in different types of cancers, we suggest in these cases that TGF-β could be an interesting therapy and strategy to induce Par-4 and apoptosis in endometrial cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2011-1107