Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.
Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.
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黄芩素通过减少有氧糖酵解并通过抑制缺氧诱导因子 1 α 逆转线粒体功能障碍，使对他莫昔芬耐药的乳腺癌细胞重新敏感
DOI：
10.1002/ctm2.577
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发表时间：
2021-11
影响因子：
10.6
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Chen Y;Zhang J;Zhang M;Song Y;Zhang Y;Fan S;Ren S;Fu L;Zhang N;Hui H;Shen X
耐药是影响他莫昔芬（TAM）临床疗效的主要障碍。因此，有必要确定一种增敏剂，可用于提高TAM治疗TAM耐药乳腺癌的疗效。在这里，我们研究了黄芩苷逆转TAM抗性的能力。我们发现黄芩苷增加了TAM对TAM耐药细胞的抑制增殖和诱导凋亡的作用。它还增强了TAM诱导的NOD/SCID小鼠乳腺脂肪垫耐药细胞的生长减少，而没有引起明显的全身毒性。使用CellMiner工具和Kaplan-Meier绘图仪数据库进行的分析显示，在NCI‐60癌细胞和乳腺癌患者中，HIF‐1α表达与TAM治疗反应呈负相关。由于mRNA水平的增加和泛素介导降解的减少，HIF - 1α在TAM耐药细胞中的表达增加。黄芩素通过促进HIF - 1α与PHD2和pVHL的相互作用来降低HIF - 1α的表达，从而促进泛素连接酶介导的蛋白酶体降解，从而抑制核易位、与缺氧反应元件的结合以及HIF - 1α的转录活性。因此，黄芩素通过限制葡萄糖摄取、乳酸生成、ATP生成、乳酸/丙酮酸比值和HIF‐1α‐靶向糖酵解基因的表达，下调有氧糖酵解，从而增强TAM的抗增殖作用。此外，黄芩素干扰HIF‐1α对线粒体生物合成的抑制，增加线粒体DNA含量和线粒体数量，恢复线粒体活性氧的产生，从而增强TAM‐诱导的线粒体凋亡途径。HIF‐1α稳定剂二甲基氧allyl甘氨酸阻止了黄芩素诱导的糖酵解和线粒体生物合成的下调，降低了黄芩素逆转TAM抗性的作用。我们的研究结果表明，黄芩素是一个很有希望的候选者，通过使耐药细胞对TAM诱导的生长抑制和凋亡敏感来帮助克服TAM耐药性。黄芩素的作用机制包括抑制HIF - 1α -介导的有氧糖酵解和线粒体功能障碍。•黄芩苷具有逆转TAM抗性的能力。•黄芩素通过促进HIF - 1α与PHD2和pVHL的相互作用，降低HIF - 1α的表达和活性，促进TAM耐药细胞中泛素连接酶介导的蛋白酶体降解。•黄芩素抑制HIF‐1α介导的有氧糖酵解，减轻HIF‐1α抑制的线粒体生物合成和活性氧的产生，从而增强TAM诱导的增殖和线粒体介导的细胞凋亡。
Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM‐resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM‐resistant cells. It also enhanced the TAM‐induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan–Meier plotter database showed that HIF‐1α expression was inversely correlated with TAM therapeutic response in NCI‐60 cancer cells and breast cancer patients. HIF‐1α expression was increased in TAM‐resistant cells due to an increase in mRNA levels and reduced ubiquitin‐mediated degradation. Baicalein reduced HIF‐1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase‐mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia‐response element, and transcriptional activity of HIF‐1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF‐1α‐targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF‐1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM‐induced mitochondrial apoptotic pathway. The HIF‐1α stabilizer dimethyloxallyl glycine prevented the baicalein‐induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM‐induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF‐1α–mediated aerobic glycolysis and mitochondrial dysfunction. • Baicalein possesses the ability to reverse TAM resistance. • Baicalein reduces the expression and activity of HIF‐1α via the promotion of its interaction with PHD2 and pVHL and facilitates the ubiquitin ligase‐mediated proteasomal degradation in TAM‐resistant cells. • Baicalein inhibits HIF‐1α–mediated aerobic glycolysis and relieves HIF‐1α–restrained mitochondrial biosynthesis and reactive oxygen species generation, thereby enhancing TAM‐induced proliferation and mitochondrial‐mediated apoptosis.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
--
作者：
Jia X;Hong Q;Lei L;Li D;Li J;Mo M;Wang Y;Shao Z;Shen Z;Cheng J;Liu G
通讯作者：
Liu G
影响因子：
5.8
作者：
Leignadier, Julie;Dalenc, Florence;Silvente-Poirot, Sandrine
通讯作者：
Silvente-Poirot, Sandrine
影响因子：
2.8
作者：
Courtnay, Rupert;Ngo, Darleen C.;Karagiannis, Tom C.
通讯作者：
Karagiannis, Tom C.
影响因子：
9
作者：
Chiu, David Kung-Chun;Tse, Aki Pui-Wah;Wong, Carmen Chak-Lui
通讯作者：
Wong, Carmen Chak-Lui