Open AccessZ-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-mediated apoptosis through the induction of endoplasmic reticulum stress
Author(s) -
Seung Un Seo,
Kyoungjin Min,
Seon Min Woo,
Taeg Kyu Kwon
Publication year - 2018
Publication title -
experimental and molecular medicine/experimental and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.703
H-Index - 82
eISSN - 2092-6413
pISSN - 1226-3613
DOI - 10.1038/s12276-018-0138-6
Subject(s) - unfolded protein response , endoplasmic reticulum , chemistry , uniporter , ryanodine receptor , microbiology and biotechnology , cathepsin s , cathepsin d , apoptosis , programmed cell death , cathepsin l1 , cancer cell , xiap , cytosol , biology , biochemistry , caspase , cancer , enzyme , genetics
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 2+ channel in the ER, but an inhibitor of a mitochondrial Ca 2+ 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.