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Article
Arsenic Trioxide Induces a Beclin-1-Independent Autophagic Pathway Via Modulation of SnoN/SkiL Expression in Ovarian Carcinoma Cells
Cell Death Differ
  • Dawn M Smith, University of South Florida
  • Shetal Patel, University of South Florida
  • Fadi Raffoul, University of South Florida
  • Edward M Haller, University of South Florida
  • Gordon B. Mills, University of Texas
  • Meera Nanjundan, University of South Florida
Document Type
Article
Publication Date
12-1-2010
Keywords
  • ovarian cancer,
  • ecotropic viral integration site-1 (EVI1),
  • SnoN/SkiL,
  • transforming growth factor-β (TGFβ),
  • arsenic trioxide (As2O3),
  • apoptosis,
  • autophagy,
  • reactive oxygen species (ROS),
  • multidrug resistance protein (MRP1)
Digital Object Identifier (DOI)
https://doi.org/10.1038/cdd.2010.53
Abstract

Arsenic trioxide (As2O3), used to treat promyelocytic leukemia, triggers cell death via unknown mechanisms. To further our understanding of As2O3-induced death, we investigated 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 proteosome inhibitors, MG132 and PS-341/Velcade, suggesting that degradation occurs via the ubiquitin-proteosome 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.

Citation / Publisher Attribution

Cell Death Differ, v. 17, issue 12, p. 1867–1881

Citation Information
Dawn M Smith, Shetal Patel, Fadi Raffoul, Edward M Haller, et al.. "Arsenic Trioxide Induces a Beclin-1-Independent Autophagic Pathway Via Modulation of SnoN/SkiL Expression in Ovarian Carcinoma Cells" Cell Death Differ Vol. 17 Iss. 12 (2010) p. 1867 - 1881
Available at: http://works.bepress.com/edward_haller/13/