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

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. Cancer: Enhancing sensitivity to anti-cancer drugs A drug that inhibits a key cancer enzyme could be used in combination with anti-cancer drugs to improve sensitivity to treatment. The intracellular endoplasmic reticulum (ER) is involved in several vital processes in cells, including folding and processing proteins. Taeg Kyu Kwon at Keimyung University, Daegu, South Korea, and co-workers have demonstrated how inhibition of cathepsin S, which is expressed in many cancer cells, induces ER stress. In trials on human kidney cancer cells grafted onto mice and in vitro, the team found that ZFL (cathepsin S inhibitor) triggered transient ER stress by increasing calcium levels inside cells. Subsequent treatment with the anti-cancer drug oxaliplatin resulted in increased cancer cell death.