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

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

  • Drug Resist Updat. 2023 Oct 26:71:101014. doi: 10.1016/j.drup.2023.101014.
Yumeng Hu 1,  Yongjie Xu 2,  Ting Zhang 3,  Qianying Han 4,  Li Li 4,  Mingyang Liu 5,  Ni Li 6,  Genze Shao 7
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
  • 4 Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 5 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. Electronic address: liumy@cicams.ac.cn.
  • 6 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. Electronic address: nli@cicams.ac.cn.
  • 7 Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: gzshao@bjmu.edu.cn.
PMID: 37913652 DOI: 10.1016/j.drup.2023.101014
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.

Keywords

Cisplatin resistance; DCAF8; ERβ; Non-small cell lung cancer; PTEN.

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