Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Office of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Drug Resist Updat. 2023 Nov;71:101014. doi: 10.1016/j.drup.2023.101014. Epub 2023 Oct 26.
High levels of the estrogen receptor β (ERβ) predict poor prognosis following platinum-containing adjuvant chemotherapies in patients with non-small cell lung cancer (NSCLC). However, the precise role of ERβ remains elusive. In this study, we demonstrated that targeting ERβ could significantly increase the cytotoxicity of cisplatin both in vitro and in vivo. Mechanically, cisplatin directly binds to ERβ, which facilitates its homodimerization and nuclear translocation. ERβ activation transcriptionally represses the expression of DCAF8, an adaptor of CRL4 E3 ubiquitin ligase, which in turn attenuates the proteasomal degradation of ERβ, leading to ERβ accumulation; this positive feedback loop results in Akt activation and eventually cisplatin resistance in NSCLC through PTEN inhibition. Moreover, low expression of DCAF8 and high expression of ERβ are associated with treatment resistance in patients receiving cisplatin-containing adjuvant chemotherapy. The present results provide insights into the underlying mechanism of ERβ-induced cisplatin resistance and offer an alternative therapeutic strategy to improve the efficacy of platinum-based chemotherapy in patients with NSCLC.
高水平的雌激素受体β（ERβ）预示着非小细胞肺癌（NSCLC）患者接受含铂辅助化疗后的预后不良。然而，ERβ的确切作用仍不清楚。在这项研究中，我们证明了靶向 ERβ 可以显著增加顺铂在体外和体内的细胞毒性。从机制上讲，顺铂直接与 ERβ结合，促进其同源二聚化和核易位。ERβ 的激活转录抑制 DCAF8 的表达，DCAF8 是 CRL4 E3 泛素连接酶的衔接蛋白，从而减弱 ERβ 的蛋白酶体降解，导致 ERβ 积累；这种正反馈环导致 Akt 激活，并最终通过 PTEN 抑制导致 NSCLC 对顺铂产生耐药性。此外，DCAF8 表达低和 ERβ 表达高与接受含顺铂辅助化疗的患者的治疗耐药性相关。这些结果深入了解了 ERβ 诱导的顺铂耐药的潜在机制，并为改善 NSCLC 患者铂类化疗的疗效提供了一种替代治疗策略。
