Page 56 - D. Cancer biology

[D. Cancer biology-41]

Inhibition of cathepsin D potentiates anti-cancer drugs-induced

apoptosis via RNF183-mediated degradation of Bcl-xL in cancer cells

Kyoung-jin Min¹, Seung Un Seo², Seon Min Woo², Taeg Kyu Kwon²

¹New Drug Development Center, Deagu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea,

²Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, South Korea

Significance of cathepsin D (Cat D) is well known in relation to metastasis, angiogenesis, proliferation and
carcinogenesis in cancer. Despite the Cat D is a promising target in cancer cells, effects and underlying mechanism

of Cat D inhibition is not clear. Here, we found inhibition of Cat D enhanced anti-cancer drugs-induced apoptosis

in human carcinoma cell lines and xenograft models. Destabilization of Bcl-xL through up-regulation of E3 ligase,
RNF183, was involved in anti-cancer effect of Cat D inhibition. Cat D inhibition induced up-regulation of RNF183
expression via autophagy-dependent NF-kappaB activation. Furthermore, p62-dependent and reactive oxygen

species-independent Nrf2 activation increased proteasome activity through induction of proteasome subunits
expression (PSMA5 and PSMB5) in Cat D inhibitor-treated cells. Therefore, induction of both E3 ligase expression

and proteasome activity was related with down-regulation of Bcl-xL levels. In addition, inhibition of Cat D suppressed
cancer stem cell population, and inhibited tumor sphere formation in multiple cancer cells. Collectively, inhibition

of Cat D decreased population of cancer stem cells and sensitized cancer cells to anti-cancer drugs-induced
apoptosis through destabilization of Bcl-xL.