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

Abstract

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.

Highlights

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  Inhibition of Cat K sensitizes cancer cells to anti-cancer drugs.

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  Reduction of Raptor by inhibition of Cat K induces mitochondria dysfunction.

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  Mitochondrial ROS induction by inhibition of Cat K induces USP27X expression.

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  Up-regulation of USP27X by inhibition of Cat K stabilizes Bim protein.