title: PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status.
abstract: 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.
authors: Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH.
authors: Snehal
authors: S
authors: Dabir
authors: Amy
authors: A
authors: Kluge
authors: Karen
authors: K
authors: McColl
authors: Yu
authors: Y
authors: Liu
authors: Minh
authors: M
authors: Lam
authors: Balazs
authors: B
authors: Halmos
authors: Gary
authors: G
authors: Wildey
authors: Afshin
authors: A
authors: Dowlati
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D018832:Molecular Chaperones / Q000502:physiology*; D050828:Protein Inhibitors of Activated STAT / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases
keywords: Noxa; PIAS3; STAT3; apoptosis; lung cancer; p53
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