biostudies-literatureSeo SUKeimyung UniversityNational Research Foundation of Korea (NRF)Keimyung University (KMU)National Research Foundation of Korea115https://www.ebi.ac.uk/biostudies/studies/S-EPMC8816936biostudies-literatureUnknown13(2)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 Cell death & diseaseCathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells.PMC88169362020 Scholar Research GrantNRF-2019R1A2C2005921NRF-2021R1A4A1029238NRF-2020R1C1C1009889Seo SULee HSMin KJKim SHWoo SMJang YNam JOGabrielson EIm SSLee HHan EKwon TKfalseCathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells.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 2022-01-01T00:00:00Z2022 Feb2026-05-31T02:03:21.047Z2025-04-06T12:10:05.233ZS-EPMC88169363512173710.1038/s41419-022-04581-7