Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor.

组织蛋白酶K（Cat K）在癌细胞中表达，但Cat K对细胞凋亡的作用仍然难以捉摸。在这里，我们显示出对Cat K的抑制通过Bim的上调使人类癌细胞对抗癌药物敏感。抑制Cat K会增加USP27x的表达，而USP27x的敲低会明显阻止Cat K诱导的Bim表达的上调。此外，抑制Cat K可以诱导蛋白酶体对雷帕霉素（Raptor）哺乳动物靶标调控相关蛋白的降解。猛禽表达的下调增加了线粒体ROS的产生，并且线粒体特有的超氧化物清除剂通过抑制Cat K阻止了USP27x介导的Bim稳定。在异种移植模型中，与Cat K抑制剂（odanacatib）和肿瘤坏死因子相关的凋亡诱导配体（TRAIL）联合治疗可减少肿瘤生长并诱导细胞死亡。我们的研究结果表明，Cat K抑制作用通过USP27x介导的Bim上调和Raptor的下调来增强抗癌药的敏感性。