Zhang Yue, Song Yuxuan, Ren Shuang, Zhang Minqin, Zhang Zhao, Fan Shuangqin, Liu Xing, Peng Xiaoyu, Qi Qi, Shen Xiangchun, Chen Yan
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.
Translational Medicine Research Center of Guizhou Medical University, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China.
Oncogene. 2023 Jan;42(3):184-197. doi: 10.1038/s41388-022-02506-4. Epub 2022 Nov 18.
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.
他莫昔芬是雌激素受体阳性乳腺癌的一线治疗药物；然而，与其他治疗方法一样，其临床应用受到获得性耐药的限制。他莫昔芬耐药细胞已表现出有氧糖酵解增强；然而，这种上调背后的机制仍不清楚。在这里，我们证明了G蛋白偶联雌激素受体（GPER）通过诱导他莫昔芬耐药细胞中缺氧诱导因子-1α（HIF-1α）的表达和转录活性参与有氧糖酵解的上调。此外，GPER通过抑制HIF-1α的羟基化和泛素介导的降解来稳定HIF-1α，这与C末端水解酶-L1（UCH-L1）的上调、脯氨酰羟化酶2（PHD2）和冯·希佩尔-林道肿瘤抑制蛋白（pVHL）的下调、HIF-1α/UCH-L1相互作用的诱导以及HIF-1α/PHD2-pVHL结合的抑制有关。GPER/HIF-1α轴在体外和体内功能上负责调节他莫昔芬的敏感性。此外，临床乳腺癌组织中GPER与HIF-1α表达之间存在正相关，高水平的GPER与核HIF-1α结合表明总生存期较差。高水平的GPER/HIF-1α轴也与接受他莫昔芬治疗的患者无复发生存期缩短相关。因此，我们的研究结果支持GPER/HIF-1α轴在他莫昔芬耐药细胞有氧糖酵解调节中的关键作用，为他莫昔芬耐药乳腺癌提供了一个潜在的治疗靶点。
