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KMID : 0620920180500080107
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Experimental & Molecular Medicine
2018 Volume.50 No. 8 p.107 ~ p.107
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Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress
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Seo Seung-Un
Min Kyoung-Jin
Woo Seon-Min
Kwon Taeg-Kyu
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Abstract
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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 Ca2+ channel in the ER, but an inhibitor of a mitochondrial Ca2+ 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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KEYWORD
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Apoptosis, Chemotherapy
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