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酶激活丙酮酸激酶增加胞质草酰乙酸以抑制瓦博格效应。

Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.

机构信息

Molecular Pharmacology and Experimental Therapeutics Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

出版信息

Nat Metab. 2021 Jul;3(7):954-968. doi: 10.1038/s42255-021-00424-5. Epub 2021 Jul 5.

DOI:10.1038/s42255-021-00424-5
PMID:34226744
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8316326/
Abstract

Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases de novo synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement of human LDHA with rabbit LDHA, which is relatively resistant to OAA inhibition, eliminated the paradoxical correlation between the elevated PKM2 activity and the decreased lactate concentration in cancer cells treated with a PKM2 activator. Furthermore, rabbit LDHA-expressing tumours, compared to human LDHA-expressing tumours in mice, displayed resistance to the PKM2 activator. These findings describe a mechanistic explanation for the PKM2 paradox by showing that OAA accumulates and inhibits LDHA following PKM2 activation.

摘要

在癌细胞中，糖酵解酶 PKM2 的药理学激活或组成型激活的 PKM1 同工型的表达导致乳酸产量降低，这在瓦伯格效应中被称为 PKM2 悖论。在这里，我们表明草酰乙酸 (OAA) 是人乳酸脱氢酶 A (LDHA) 的竞争性抑制剂，并且升高的 PKM2 活性通过谷氨酰胺分解增加 OAA 的从头合成，从而抑制癌细胞中的 LDHA。我们还表明，用人 LDHA 替换相对不易受 OAA 抑制的兔 LDHA，消除了在用 PKM2 激活剂处理的癌细胞中升高的 PKM2 活性与降低的乳酸浓度之间的矛盾相关性。此外，与在小鼠中表达人 LDHA 的肿瘤相比，表达兔 LDHA 的肿瘤对 PKM2 激活剂表现出抗性。这些发现通过表明 PKM2 激活后 OAA 积累并抑制 LDHA，为 PKM2 悖论提供了一种机制解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c2d/8316326/d37e83a3e39f/nihms-1711941-f0007.jpg
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