Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells

D. M. Smith, S. Patel, F. Raffoul, E. Haller, G. B. Mills, M. Nanjundan

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Arsenic trioxide (As2O3), used to treat promyelocytic leukemia, triggers cell death through unknown mechanisms. To further our understanding of As2O3-induced death, we analyzed its effects on transforming growth factor-Β (TGFΒ) signaling mediators in ovarian cells. Dysregulated TGFΒ signaling is a characteristic of ovarian cancers. As2O3 reduced the protein expression of EVI1, TAK1, SMAD2/3, and TGFΒRII while increasing SnoN/SkiL. EVI1 protein was modulated by treatment with the proteasome inhibitors, MG132 and PS-341/Velcade, suggesting that degradation occurs through the ubiquitin-proteasome pathway. The sensitivity of ovarian cells to As2O3-induced apoptosis correlated with expression of multidrug resistance protein 1. Interestingly, expression of SnoN was similar to LC3-II (autophagy marker), which increased with induction of cytoplasmic vacuolation preceding apoptosis. These vesicles were identified as autophagosomes based on transmission electron microscopy and immunofluorescence staining with EGFP-LC3. The addition of N-acetyl-L-cysteine (ROS scavenger) to As2O3-treated cells reversed changes in SnoN protein and the autophagic/apoptotic response. In contrast to beclin-1 knockdown, siRNA targeting ATG5, ATG7, and hVps34 markedly reduced autophagy in As2O3-treated ovarian carcinoma cells. Further, treatment with SnoN siRNA markedly decreased LC3-II levels and increased PARP degradation (an apoptosis marker). Collectively, these findings suggest that As2O3 induces a beclin-1-independent autophagic pathway in ovarian carcinoma cells and implicates SnoN in promoting As2O3-mediated autophagic cell survival.

Original languageEnglish (US)
Pages (from-to)1867-1881
Number of pages15
JournalCell Death and Differentiation
Volume17
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

Keywords

  • SnoN/SkiL
  • arsenic trioxide (As O)
  • autophagy
  • ecotropic viral integration site-1 (EVI1)
  • ovarian cancer
  • transforming growth factor-β (TGFβ)

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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