Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, 200032, China.
Int J Biol Sci. 2022 Feb 7;18(4):1724-1736. doi: 10.7150/ijbs.66480. eCollection 2022.
Chemoresistance is closely related to the therapeutic effect and prognosis in breast cancer patients. Increasing evidences demonstrated that RNA binding proteins (RBPs) have notable roles in regulating cancer cell proliferation, metastasis and chemotherapeutic sensitivity. RNA binding motif single stranded interacting protein 2 (RBMS2), an RBP, has been considered to be a tumor suppressor in several cancers. However, its role of doxorubicin sensitivity in breast cancer patients has not yet been fully revealed. Here, we performed doxorubicin cytotoxicity assay, flow cytometry and mouse xenograft model to examine the influence of RBMS2 on doxorubicin sensitization and . RIP assay and dual-luciferase reporter assay were performed to explore the relationship between RBMS2 and BMF. Our data demonstrated that upregulation of RBMS2 in breast cancer cells could enhance sensitivity to doxorubicin and promote apoptosis in the presence of doxorubicin, while inhibition of RBMS2 showed an opposite trend. Moreover, this chemosensitizing effect of RBMS2 could be reversed by the inhibition of Bcl-2 modifying factor (BMF). RBMS2 positively regulated BMF expression and increased BMF-induced expression of (cleaved) caspase 3, (cleaved) caspase 9 and poly (ADP-Ribose) polymerase (PARP). These results uncovered a novel mechanism for RBMS2 in the sensibilization of doxorubicin, suggesting that RBMS2 may act as a potential therapeutic target for drug-resistant breast cancer.
耐药性与乳腺癌患者的治疗效果和预后密切相关。越来越多的证据表明，RNA 结合蛋白（RBPs）在调节癌细胞增殖、转移和化疗敏感性方面发挥着重要作用。RNA 结合基序单链相互作用蛋白 2（RBMS2）是一种 RBP，在几种癌症中被认为是一种肿瘤抑制因子。然而，其在乳腺癌患者中对多柔比星敏感性的作用尚未完全揭示。在这里，我们进行了多柔比星细胞毒性测定、流式细胞术和小鼠异种移植模型，以研究 RBMS2 对多柔比星增敏作用的影响。进行了 RIP 测定和双荧光素酶报告基因测定，以探讨 RBMS2 与 BMF 之间的关系。我们的数据表明，乳腺癌细胞中 RBMS2 的上调可以增强多柔比星的敏感性，并在多柔比星存在的情况下促进细胞凋亡，而 RBMS2 的抑制则呈现相反的趋势。此外，RBMS2 的这种化疗增敏作用可以被 Bcl-2 修饰因子（BMF）的抑制所逆转。RBMS2 正向调节 BMF 的表达，并增加 BMF 诱导的（裂解）半胱天冬酶 3、（裂解）半胱天冬酶 9 和多聚（ADP-核糖）聚合酶（PARP）的表达。这些结果揭示了 RBMS2 在多柔比星增敏中的新机制，表明 RBMS2 可能作为耐药性乳腺癌的潜在治疗靶点。
