BRCA1丝氨酸1387磷酸化在细胞色素酶S介导的辐射抗性中的关键作用：通过BRCA1降解和BCL2稳定实现

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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

影响因子:4.2

分区:生物学2区 / 生物物理2区生化与分子生物学3区

发表日期:2025 Jan

作者: Gil-Im Mun, Eun Choi, Hee Jin, Seul-Ki Choi, Hanhee Lee, Seoyoung Kim, Junghyun Kim, Chaerin Kang, Hye Lim Oh, Hae-June Lee, Dae-Ro Ahn, Yun-Sil Lee

DOI: 10.1016/j.bbadis.2024.167523

摘要

已有证据表明，BRCA1，特别是细胞质BRCA1，在启动细胞凋亡过程中发挥重要作用，机制多样。在癌细胞中维持BRCA1的稳定性可能是乳腺癌，尤其是缺乏合适治疗靶点的三阴性乳腺癌（TNBC）的一种有前景的治疗策略。此前报道，半胱天冬酶S（CTSS）与BRCA1的BRCT结构域相互作用，导致通过泛素介导的降解。我们进一步研究了由电离辐射（IR）激活的ATM介导的BRCA1在Ser1387位点的磷酸化作用，此磷酸化事件被确认是CTSS介导的BRCA1泛素降解的关键因素。通过小分子抑制剂或敲除系统抑制CTSS，能在辐射治疗中增强TNBC细胞的敏感性，原因在于恢复细胞质BRCA1的稳定性。细胞质BRCA1的增加促使抗凋亡蛋白BCL2的降解，这是CTSS抑制引起的辐射增强效应的基础。这些结果表明，抑制CTSS可能成为通过抑制BRCA1降解、促进BCL2降解而实现TNBC细胞辐射敏感化的有效策略。

Abstract

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.