Cathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells

• Published in: Cell death & disease Vol. 13; no. 2; p. 115
• Main Authors: Seo, Seung Un, Woo, Seon Min, Im, Seung-Soon, Jang, Younghoon, Han, Eugene, Kim, Sang Hyun, Lee, Hongchan, Lee, Hyun-Shik, Nam, Ju-Ock, Gabrielson, Edward, Min, Kyoung-jin, Kwon, Taeg Kyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-02-2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/2; 13/31; 13/89; 14/19; 631/67/1059/602; 631/80/82/23; 82; 82/80; Angiogenesis; Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis; Bcl-x protein; bcl-X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer; Carcinogenesis; Carcinoma, Renal Cell - drug therapy; Cathepsin D; Cathepsin D - antagonists & inhibitors; Cell Biology; Cell Culture; Cell Line, Tumor; Drug development; Humans; Immunology; Kidney Neoplasms - drug therapy; Kinases; Life Sciences; Metastases; NF-κB protein; Proteasome Endopeptidase Complex; Proteasomes; Proto-Oncogene Proteins c-bcl-2 - metabolism; Renal cell carcinoma; Therapeutic targets; Tumor cell lines; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04581-7

Cathepsin D (Cat D) is well known for its roles in metastasis, angiogenesis, proliferation, and carcinogenesis in cancer. Despite Cat D being a promising target in cancer cells, effects and underlying mechanism of its inhibition remain unclear. Here, we investigated the plausibility of using Cat D inhibition as an adjuvant or sensitizer for enhancing anticancer drug-induced apoptosis. Inhibition of Cat D markedly enhanced anticancer drug-induced apoptosis in human carcinoma cell lines and xenograft models. The inhibition destabilized Bcl-xL through upregulation of the expression of RNF183, an E3 ligase of Bcl-xL, via NF-κB activation. Furthermore, Cat D inhibition increased the proteasome activity, which is another important factor in the degradation of proteins. Cat D inhibition resulted in p62-dependent activation of Nrf2, which increased the expression of proteasome subunits (PSMA5 and PSMB5), and thereby, the proteasome activity. Overall, Cat D inhibition sensitized cancer cells to anticancer drugs through the destabilization of Bcl-xL. Furthermore, human renal clear carcinoma (RCC) tissues revealed a positive correlation between Cat D and Bcl-xL expression, whereas RNF183 and Bcl-xL expression indicated inverse correlation. Our results suggest that inhibition of Cat D is promising as an adjuvant or sensitizer for enhancing anticancer drug-induced apoptosis in cancer cells.