Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization.

Autor: Mun GI; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Choi E; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Jin H; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Choi SK; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Lee H; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Kim S; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea; New Horizon Cancer Institute, Myongji Hospital, Seoul 10472, Republic of Korea., Kim J; Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea., Kang C; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Oh HL; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea., Lee HJ; Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea., Ahn DR; Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea., Lee YS; Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: yslee0425@ewha.ac.kr.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Sep 25; Vol. 1871 (1), pp. 167523. Date of Electronic Publication: 2024 Sep 25.
DOI: 10.1016/j.bbadis.2024.167523
Abstrakt: There is evidence that BRCA1, particularly cytoplasmic BRCA1, plays a significant role in initiating apoptosis through various mechanisms. Maintaining the stability of BRCA1 in cancer cells may be a promising therapeutic strategy for breast cancer, especially in cases of triple-negative breast cancer (TNBC) lacking appropriate therapeutic targets. Previously, it was reported that cathepsin S (CTSS) interacts with the BRCT domain of BRCA1, leading to ubiquitin-mediated degradation. We further investigated the critical role of BRCA1 phosphorylation at Ser1387, which is mediated by ionizing radiation (IR)-induced activation of ATM. This phosphorylation event was identified as a key factor in CTSS-mediated ubiquitin degradation of BRCA1. The functional inhibition of CTSS, using small molecules or a knockdown system, sensitized TNBC cells when exposed to IR by restoring the stability of cytoplasmic BRCA1. The increase in cytoplasmic BRCA1 led to the degradation of anti-apoptotic BCL2, which was responsible for the radiosensitization effect observed with CTSS inhibition. These results suggest that inhibiting CTSS may be an effective strategy for radiosensitization in TNBC cells through BCL2 degradation that is mediated by inhibition of CTSS-induced BRCA1 degradation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. TNBC cell lines were exposed to irradiation (10 Gy) after pre-treatment with CTSS inhibitors; RO5461111 (RO) and Z-FL-COCHO (Z-FL). TNBC cell lines with wild-type BRCA1 (WT); MDA-MB-231 (231) & HCC70 and mutant BRCA1 (MT); MDA-MB-436 (436) & HCC1937 (1937). (A) Western blot analysis and the quantification of cleaved-PARP1 induction; (B) Cell death was evaluated with PI staining. Results are the means and SD (*p < 0.05, ANOVA).
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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