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

作者：Smith D M; Patel S; Raffoul F; Haller E; Mills G B; Nanjundan M^*

来源：Cell Death and Differentiation, 2010, 17(12): 1867-1881.

DOI：10.1038/cdd.2010.53

• ovarian cancer, ecotropic viral integration site-1 (EVI1)
• SnoN/SkiL
• transforming growth factor-beta (TGF beta)
• arsenic trioxide (As(2)O(3))
• autophagy

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-beta (TGF beta) signaling mediators in ovarian cells. Dysregulated TGF beta signaling is a characteristic of ovarian cancers. As(2)O(3) reduced the protein expression of EVI1, TAK1, SMAD2/3, and TGF beta RII 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. Cell Death and Differentiation (2010) 17, 1867-1881; doi:10.1038/cdd.2010.53; published online 28 May 2010

• 出版日期2010-12