Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer
Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer
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DOI：
10.1016/j.celrep.2019.05.066
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发表时间：
2019-06-18
期刊：
影响因子：
8.8
通讯作者：
McDonnell, Donald P.
中科院分区：
文献类型：
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作者：
Park, Sunghee;Safi, Rachid;McDonnell, Donald P.
大多数癌细胞表现出代谢灵活性，使它们能够承受肿瘤内葡萄糖（和其他营养物质）浓度的波动和氧气可用性的变化。虽然这些适应性反应使得在针对单一代谢途径时难以实现临床有用的抗肿瘤反应，但它们也可以作为可靶向的代谢脆弱性，可以在治疗上加以利用。在此之前，我们证明了抑制雌激素相关受体α (ERR α)会显著破坏线粒体代谢，从而在乳腺癌动物模型中产生实质性的抗肿瘤活性。在这里，我们发现ERR α抑制通过抑制线粒体丙酮酸载体1 （MPC1）的表达来干扰丙酮酸进入线粒体。这导致细胞对谷氨酰胺氧化和戊糖磷酸途径的依赖急剧增加，以维持烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的稳态。通过这种方式，ERR α抑制增加了谷氨酰胺酶和葡萄糖-6-磷酸脱氢酶抑制剂的疗效，这一发现具有临床意义。
Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of estrogen-related receptor alpha (ERR alpha) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERR alpha inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERR alpha inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.