Cisplatin-activated ERβ/DCAF8 positive feedback loop induces chemoresistance in non-small cell lung cancer via PTEN/Akt axis

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2023-11-01 DOI:10.1016/j.drup.2023.101014
Yumeng Hu , Yongjie Xu , Ting Zhang , Qianying Han , Li Li , Mingyang Liu , Ni Li , Genze Shao
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Abstract

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.

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顺铂激活的ERβ/DCAF8正反馈回路通过PTEN/Akt轴诱导癌症化疗耐药性。
高水平的雌激素受体β(ERβ)可预测癌症(NSCLC)患者接受含铂辅助化疗后的不良预后。然而,ERβ的确切作用仍然难以捉摸。在本研究中,我们证明靶向ERβ可以在体外和体内显著增加顺铂的细胞毒性。在机制上,顺铂直接与ERβ结合,促进其同源二聚和核转位。ERβ激活转录抑制DCAF8的表达,DCAF8是CRL4 E3泛素连接酶的衔接子,进而减弱ERβ的蛋白酶体降解,导致ERβ积累;这种正反馈回路通过PTEN抑制导致NSCLC中的Akt激活并最终导致顺铂耐药性。此外,DCAF8的低表达和ERβ的高表达与接受含顺铂辅助化疗的患者的治疗耐药性有关。目前的结果为ERβ诱导的顺铂耐药性的潜在机制提供了见解,并为提高非小细胞肺癌患者铂类化疗的疗效提供了一种替代治疗策略。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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