Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization

• Published in: Redox biology 2020-02, Vol.30, p.101422, Article 101422
• Main Authors: Seo, Seung Un, Woo, Seon Min, Kim, Min Wook, Lee, Hyun-Shik, Kim, Sang Hyun, Kang, Sun Chul, Lee, Eun-Woo, Min, Kyoung-jin, Kwon, Taeg Kyu
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Bcl-2-Like Protein 11 - chemistry; Bcl-2-Like Protein 11 - metabolism; Bim; Biphenyl Compounds - pharmacology; Cathepsin K; Cathepsin K - antagonists & inhibitors; Cathepsin K - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Synergism; Gene Expression Regulation, Neoplastic - drug effects; HeLa Cells; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Male; Mice; Mitochondria; Mitochondria - metabolism; Protein Stability; Raptor; Reactive Oxygen Species - metabolism; Research Paper; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Ubiquitin-Specific Proteases - metabolism; USP27x; Xenograft Model Antitumor Assays
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2019.101422

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. •Inhibition of Cat K sensitizes cancer cells to anti-cancer drugs.•Reduction of Raptor by inhibition of Cat K induces mitochondria dysfunction.•Mitochondrial ROS induction by inhibition of Cat K induces USP27X expression.•Up-regulation of USP27X by inhibition of Cat K stabilizes Bim protein.