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Cathepsin D as a potential therapeutic target to enhance anticancer drug-induced apoptosis via RNF183-mediated destabilization of Bcl-xL in cancer cells.
- Source :
-
Cell death & disease [Cell Death Dis] 2022 Feb 04; Vol. 13 (2), pp. 115. Date of Electronic Publication: 2022 Feb 04. - Publication Year :
- 2022
-
Abstract
- 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.<br /> (© 2022. The Author(s).)
- Subjects :
- Apoptosis
Cell Line, Tumor
Humans
Proteasome Endopeptidase Complex
Proto-Oncogene Proteins c-bcl-2 metabolism
bcl-X Protein metabolism
Antineoplastic Agents pharmacology
Carcinoma, Renal Cell drug therapy
Cathepsin D antagonists & inhibitors
Kidney Neoplasms drug therapy
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 35121737
- Full Text :
- https://doi.org/10.1038/s41419-022-04581-7