PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status

Snehal Dabir, Amy Kluge, Karen McColl, Yu Liu, Minh Lam, Balazs Halmos, Gary Wildey, Afshin Dowlati

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1045-1054
Number of pages10
JournalInternational Journal of Cancer
Volume134
Issue number5
DOIs
StatePublished - Mar 1 2014
Externally publishedYes

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STAT3 Transcription Factor
Non-Small Cell Lung Carcinoma
Noxae
Apoptosis
Poly(ADP-ribose) Polymerases
Caspase 9
Growth
Cytochromes c
Transcriptome
Caspase 3
Small Interfering RNA
Squamous Cell Carcinoma
Lung Neoplasms
Cell Line
Lung
Genes
Proteins

Keywords

  • apoptosis
  • lung cancer
  • Noxa
  • p53
  • PIAS3
  • STAT3

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. / Dabir, Snehal; Kluge, Amy; McColl, Karen; Liu, Yu; Lam, Minh; Halmos, Balazs; Wildey, Gary; Dowlati, Afshin.

In: International Journal of Cancer, Vol. 134, No. 5, 01.03.2014, p. 1045-1054.

Research output: Contribution to journalArticle

Dabir, Snehal ; Kluge, Amy ; McColl, Karen ; Liu, Yu ; Lam, Minh ; Halmos, Balazs ; Wildey, Gary ; Dowlati, Afshin. / PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status. In: International Journal of Cancer. 2014 ; Vol. 134, No. 5. pp. 1045-1054.
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