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
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GPER 介导的 HIF-1α 稳定有助于上调他莫昔芬耐药细胞的有氧糖酵解
DOI：
10.1038/s41388-022-02506-4
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发表时间：
2022-11
期刊：
影响因子：
8
通讯作者：
Yan Chen
中科院分区：
文献类型：
--
作者：
Yue Zhang;Yuxuan Song;Shuang Ren;Minqin Zhang;Zhao Zhang;Shuangqin Fan;Xing Liu;Xiaoyu Peng;Qi Qi;Xiangchun Shen;Yan Chen
他莫昔芬是治疗雌激素受体阳性乳腺癌的一线药物；然而，像其他治疗药物一样，它的临床应用受到获得性耐药性的限制。他莫昔芬耐药细胞表现出增强的有氧糖酵解；然而，这种上调的机制尚不清楚。在此，我们证明G蛋白偶联雌激素受体通过诱导耐药细胞中缺氧诱导因子-1α(HIF-1α)的表达和转录活性而参与有氧糖酵解的上调。此外，GPER通过抑制其羟化和泛素介导的降解来稳定HIF-1α，这与上调C-末端水解酶-L1(Uch-L1)、下调Pro-2和von Hippel-Lindau肿瘤抑制蛋白(PVHL)、诱导HIF-1α/Uch-L1相互作用和抑制HIF-1α/PHD2-pVHL关联有关。GPER/HIF-1α轴在体外和体内均参与调节他莫昔芬的敏感性。此外，临床乳腺癌组织中GPER与HIF-1α的表达呈正相关，GPER与核HIF-1α的高表达提示总体生存率较低。在接受他莫昔芬治疗的患者中，GPER/HIF-1α轴的高水平也与较短的无复发生存期相关。因此，我们的发现支持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。
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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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1186/s13058-017-0923-5
发表时间：
2017-12-06
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
De Francesco EM;Sims AH;Maggiolini M;Sotgia F;Lisanti MP;Clarke RB
通讯作者：
Clarke RB
DOI：
10.1186/bcr3609
发表时间：
2014-01-29
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kazi AA;Gilani RA;Schech AJ;Chumsri S;Sabnis G;Shah P;Goloubeva O;Kronsberg S;Brodie AH
通讯作者：
Brodie AH
DOI：
10.1186/s13058-015-0579-y
发表时间：
2015-05-21
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Yuan J;Liu M;Yang L;Tu G;Zhu Q;Chen M;Cheng H;Luo H;Fu W;Li Z;Yang G
通讯作者：
Yang G
影响因子：
2.6
作者：
Ignatov, Tanja;Treeck, Oliver;Ignatov, Atanas
通讯作者：
Ignatov, Atanas