Premium
PIAS3 activates the intrinsic apoptotic pathway in non‐small cell lung cancer cells independent of p53 status
Author(s) -
Dabir Snehal,
Kluge Amy,
McColl Karen,
Liu Yu,
Lam Minh,
Halmos Balazs,
Wildey Gary,
Dowlati Afshin
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28448
Subject(s) - stat3 , apoptosis , cancer research , stat protein , biology , cell growth , activator (genetics) , cell , microbiology and biotechnology , signal transduction , repressor , transcription factor , gene , biochemistry
Protein inhibitor of activated signal transducer and activator of transcription 3 (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 this study, we sought to determine whether PIAS3 inhibits cell growth in non‐small cell lung cancer cell lines by inducing apoptosis. Our results demonstrate that overexpression of PIAS3 promotes mitochondrial depolarization, leading to cytochrome c release, caspase 9 and 3 activation and poly (ADP‐ribose) polymerase cleavage. This intrinsic pathway activation was associated with decreased Bcl‐xL expression and increased Noxa expression and was independent of p53 status. Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to discover STAT3‐independent mediators of PIAS3‐induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 overexpression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes was uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53‐independent efficacy and its potential to synergize with Bcl‐2 targeted inhibitors.