Arsenic Trioxide Induces a Beclin-1-Independent Autophagic Pathway Via Modulation of SnoN/SkiL Expression in Ovarian Carcinoma Cells
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)
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?
Citation / Publisher Attribution
Cell Death Differ, v. 17, issue 12, p. 1867–1881
Scholar Commons Citation
Smith, Dawn M.; Patel, Shetal; Raffoul, Fadi; Haller, Edward M.; Mills, Gordon B.; and Nanjundan, Meera, "Arsenic Trioxide Induces a Beclin-1-Independent Autophagic Pathway Via Modulation of SnoN/SkiL Expression in Ovarian Carcinoma Cells" (2010). Integrative Biology Faculty and Staff Publications. 270.