Abstract
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.
Highlights
Introduction CathepsinS is a lysosomal cysteine protease highly expressed in antigen-presenting cells (B cells, macrophages, microglia, and dendritic cells)[1,2,3,4]
We investigated whether the downregulation of cathepsin S by small interfering RNA (siRNA) modulates the expression of GRP78, ATF4, REDD1, and CHOP in a manner similar to ZFL treatment
We found that ZFL induced endoplasmic reticulum (ER) stress responses, but ZFL did not induce poly (ADP-ribose) polymerase (PARP)
Summary
S is a lysosomal cysteine protease highly expressed in antigen-presenting cells (B cells, macrophages, microglia, and dendritic cells)[1,2,3,4]. The main function of this protease is the degradation of the class II major histocompatibility complex-associated invariant chain, which is related to the immune response[4]. Cathepsin S is detected in malignant cells[5,6,7], and many researchers have suggested the pro-tumoral effects of cathepsin S in cancer cells. Cathepsin S plays critical roles mice crossed with the spontaneous pancreatic beta-cell carcinogenesis model (RIP1-Tag2) exhibited impaired tumor growth and angiogenesis[13]. The expression level of cathepsin S is related to poor outcomes in glioblastoma[14], lung cancer[15], and colorectal cancer[16]
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