Title

Arsenic Trioxide Induces a Beclin-1-Independent Autophagic Pathway Via Modulation of SnoN/SkiL Expression in Ovarian Carcinoma Cells

Document Type

Article

Publication Date

12-2010

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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

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

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