Abstract 847: PIAS3 induction of apoptosis is p53-independent and has STAT3-independent mediators.

Abstract

Abstract Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by induction of apoptosis and further determine the dependence of PIAS3 activity on p53 status by using both wild-type and p53-null cells. Our results demonstrate that over-expression of PIAS3 promotes caspase 3 activation and PARP cleavage. Furthermore, the expression of pro-survival family members BclXL and Bcl-2 is decreased. These effects were observed after both transient and regulated expression of exogenous PIAS3 and were independent of p53 status. PIAS3 inhibition of STAT3 luciferase activity was also p53 independent. Microarray experiments were performed to further investigate the STAT3-dependence of PIAS3-induced apoptosis by comparing its gene expression signature with that of STAT3 siRNA treated cells. IPA pathway analysis showed that a number of genes related to cell death were significantly increased by PIAS3. Furthermore, a subset of apoptotic genes, including CIDEC and DAPK2, were uniquely expressed only after PIAS3 expression and not after STAT3 siRNA. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with direct STAT3 inhibitors. Citation Format: Snehal Dabir, Yu Liu, Gary Wildey, Afshin Dowlati. PIAS3 induction of apoptosis is p53-independent and has STAT3-independent mediators. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 847. doi:10.1158/1538-7445.AM2013-847