丝氨酸1387处BRCA1的磷酸化在通过BRCA1降解和BCL2稳定的组织蛋白酶S介导的辐射抗性中起关键作用
Phosphorylation of BRCA1 at serine 1387 plays a critical role in cathepsin S-mediated radiation resistance via BRCA1 degradation and BCL2 stabilization
影响因子:4.20000
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
摘要
有证据表明，BRCA1，尤其是细胞质BRCA1，在通过各种机制引发凋亡中起着重要作用。在癌细胞中保持BRCA1的稳定性可能是乳腺癌的有前途的治疗策略，尤其是在缺乏适当治疗靶点的三阴性乳腺癌（TNBC）的情况下。以前，据报道，组织蛋白酶（CTSS）与BRCA1的BRCT结构域相互作用，从而导致泛素介导的降解。我们进一步研究了BRCA1磷酸化在Ser1387上的关键作用，该磷酸化是通过电离辐射（IR）诱导的ATM激活介导的。该磷酸化事件被确定为CTSS介导的BRCA1泛素降解的关键因素。通过恢复细胞质BRCA1的稳定性，使用小分子或敲低系统的CTSS功能抑制，使TNBC细胞敏感。细胞质BRCA1的增加导致抗凋亡BCL2的降解，这是导致通过CTSS抑制观察到的放射性敏感效应。这些结果表明，抑制CTS可能是通过BCL2降解在TNBC细胞中放射敏化的有效策略，该降解是通过抑制CTSS诱导的BRCA1降解介导的。
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.