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Arsenite-induced apoptosis can be attenuated via depletion of mTOR activity to restore autophagy

Abstract

Arsenic is and its compounds are toxic environmental pollutants and known carcinogens. We investigated here the mechanism of arsenite-induced damage in renal cells. Treating human embryonic kidney cells (HEK293) with sodium arsenite reduces cell viability in a dose- and time-dependent manner. The decline of cell viability is due to apoptotic death since arsenite treatment reduces Akt activity and Bcl2 level but increases caspase 3 activity and cytochrome c level. These effects can be reverted by the addition of apoptosis inhibitor. PTEN, the upstream negative regulator of Akt activity, was also reduced with arsenite treatment. Noticeably, PTEN markedly increased in the insoluble fraction of the cells, suggesting a cell failure in removing the damaged proteins. Arsenite treatment activates a variety of signaling factors. Among them, ERK and JNK are associated with autophagy via regulating the levels of LC3 and p62. With arsenite administration, LC3 and p62 levels increased. However, lysosomal activity was decreased and led to the decline of autophagotic activity. Addition of rapamycin, the mTOR inhibitor, activated the autophagotic pathway that accelerated the removal of damaged proteins. The recovery of autophagy increased the viability of arsenite-treated cells. Similar to rapamycin treatment, knockdown of mTOR expression also enhanced the viability of arsenite-treated cells. Both rapamycin treatment and mTOR knockdown enhanced ERK activity further, but reduced JNK activity and p62 level in arsenite-treated cells. Lysosomal activity increased with the depletion of mTOR, indicating an increase of autophagotic activity. These results reveal the critical role of mTOR in regulating the cell fate of arsenite-exposed renal cells.

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Publication details

The article was received on 05 Sep 2018, accepted on 29 Oct 2018 and first published on 30 Oct 2018


Article type: Paper
DOI: 10.1039/C8TX00238J
Citation: Toxicol. Res., 2018, Accepted Manuscript
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    Arsenite-induced apoptosis can be attenuated via depletion of mTOR activity to restore autophagy

    C. Wu, P. Lin, J. Tsai, C. Lin and L. Lin, Toxicol. Res., 2018, Accepted Manuscript , DOI: 10.1039/C8TX00238J

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