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Cell Death Differ. 2010 Dec;17(12):1867-81. doi: 10.1038/cdd.2010.53. Epub 2010 May 28.

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

Author information

1
Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, BSF218, Tampa, FL, USA.

Abstract

Arsenic trioxide (As(2)O(3)), used to treat promyelocytic leukemia, triggers cell death through unknown mechanisms. To further our understanding of As(2)O(3)-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. As(2)O(3) 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 As(2)O(3)-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 As(2)O(3)-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 As(2)O(3)-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 As(2)O(3) induces a beclin-1-independent autophagic pathway in ovarian carcinoma cells and implicates SnoN in promoting As(2)O(3)-mediated autophagic cell survival.

PMID:
20508647
PMCID:
PMC2932795
DOI:
10.1038/cdd.2010.53
[Indexed for MEDLINE]
Free PMC Article

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