Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress.

Exp Mol Med 2018 08 17;50(8):107. Epub 2018 Aug 17.

Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea.

Multiple cancer cells highly express cathepsin S, which has pro-tumoral effects. However, it was previously unknown whether knockdown or a pharmacological inhibitor (ZFL) of cathepsin S acts as an inducer of ER stress. Here, ZFL and knockdown of cathepsin S markedly induced ER stress through the up-regulation of calcium levels in the cytosol. Induction of calcium levels by inhibition of cathepsin S is markedly blocked by an inhibitor of the IP3 receptor and the ryanodine receptor Ca channel in the ER, but an inhibitor of a mitochondrial Ca uniporter had no effect on ZFL-induced calcium levels. Furthermore, production of mitochondrial ROS by ZFL was associated with an increase in cytosolic calcium levels. ZFL-mediated ER stress enhanced anti-cancer drug-induced apoptotic cell death, and pretreatment with chemical chaperones or down-regulation of ATF4 and CHOP by small interfering RNA markedly reduced ZFL plus oxaliplatin-induced apoptosis. Taken together, our findings reveal that inhibition of cathepsin S is an inducer of ER stress; these findings may contribute to the enhancement of therapeutic efficiency in cancer cells.

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Source
http://www.nature.com/articles/s12276-018-0138-6
Publisher Site
http://dx.doi.org/10.1038/s12276-018-0138-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098103PMC
August 2018

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