Page 147 - D. Cancer biology

Inhibition of cathepsin K sensitizes anti-cancer drugs-induced cancer
cell death through USP27x-mediated Bim Protein stabilization
Seung Un Seo, Kyoung-jin Min and Taeg Kyu Kwon*

Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea.
BACKGROUND AIM

Cathepsin (Cat) K belongs to the papain-like cysteine Increased expression of Cats makes cancer cells more sensitive to
proteases and is mainly located in the lysosomes. Cat K cathepsin inhibitors. Although it is known that Cat K modulates invasion
was originally considered to regulate bone homeostasis in and metastasis through degradation of matrix proteins in melanoma, it is
still unclear whether Cat K plays additional roles in cancer cells. In view
osteoclasts. However, Cat K is also detected in other cells, of this evidence, in this study, we investigated the effect of Cat K
such as fibroblasts, chondrocytes, neurons, and astrocytes, inhibition on cell death, and the related molecular mechanisms were
and its expression increases in cancers. evaluated in human renal carcinoma Caki cells.

RESULTS
Figure 1 Figure 2 Figure 3

Figure 4 Figure 5 Figure 6

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 Kinduced 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 anticancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor.
CONCLUSION REFERENCES ACKNOWLEDGEMENTS

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