Page 148 - D. Cancer biology

[D. Cancer biology-96]

Inhibition of cathepsin K sensitizes anti-cancer drugs-induced

cancer cell death through USP27x-mediated Bim protein

stabilization

Seung Un Seo¹, Kyoung-jin Min¹, Taeg Kyu Kwon¹

¹Immunology, Keimyung University, Daegu 42601, Korea

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.