2. Academic Validation
  3. GPER-mediated stabilization of HIF-1α contributes to upregulated aerobic glycolysis in tamoxifen-resistant cells

GPER-mediated stabilization of HIF-1α contributes to upregulated aerobic glycolysis in tamoxifen-resistant cells

  • Oncogene. 2022 Nov 18. doi: 10.1038/s41388-022-02506-4.
Yue Zhang # 1,  Yuxuan Song # 1 2 3,  Shuang Ren # 1 2 3,  Minqin Zhang # 1 2 3,  Zhao Zhang 4,  Shuangqin Fan 1 2 3,  Xing Liu 1 2 3,  Xiaoyu Peng 1 2 3,  Qi Qi 5,  Xiangchun Shen 6 7 8,  Yan Chen 9 10 11
Affiliations

Affiliations

  • 1 The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China.
  • 2 Translational Medicine Research Center of Guizhou Medical University, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China.
  • 3 The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
  • 4 Medical Examination Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China.
  • 5 MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China. qiqikc@jnu.edu.cn.
  • 6 The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China. sxc@gmc.edu.cn.
  • 7 Translational Medicine Research Center of Guizhou Medical University, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China. sxc@gmc.edu.cn.
  • 8 The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, China. sxc@gmc.edu.cn.
  • 9 The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China. chenyan@gmc.edu.cn.
  • 10 Translational Medicine Research Center of Guizhou Medical University, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China. chenyan@gmc.edu.cn.
  • 11 The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, China. chenyan@gmc.edu.cn.
  • # Contributed equally.
PMID: 36400971 DOI: 10.1038/s41388-022-02506-4
Abstract

Tamoxifen is a first-line therapeutic drug for oestrogen-receptor positive breast cancer; however, like other therapeutics, its clinical use is limited by acquired resistance. Tamoxifen-resistant cells have demonstrated enhanced aerobic glycolysis; however, the mechanisms underlying this upregulation remain unclear. Here, we demonstrated that G-protein coupled oestrogen receptor (GPER) was involved in the upregulation of aerobic glycolysis via induction of hypoxia-inducible factor-1α (HIF-1α) expression and transcriptional activity in tamoxifen-resistant cells. Additionally, GPER stabilized HIF-1α through inhibiting its hydroxylation and ubiquitin-mediated degradation, which were associated with upregulation of C-terminal hydrolase-L1 (UCH-L1), downregulation of prolyl hydroxylase 2 (PHD2) and von Hippel-Lindau tumour suppressor protein (pVHL), induction of HIF-1α/UCH-L1 interaction, and suppression of HIF-1α/PHD2-pVHL association. The GPER/HIF-1α axis was functionally responsible for regulating tamoxifen sensitivity both in vitro and in vivo. Moreover, there was a positive correlation between GPER and HIF-1α expression in clinical breast Cancer tissues, and high levels of GPER combined with nuclear HIF-1α indicated poor overall survival. High levels of the GPER/HIF-1α axis were also correlated with shorter relapse-free survival in patients receiving tamoxifen. Hence, our findings support a critical role of GPER/HIF-1α axis in the regulation of aerobic glycolysis in tamoxifen-resistant cells, offering a potential therapeutic target for tamoxifen-resistant breast Cancer.

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