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.

糖酵解酶 PKM2 的药理学激活或癌细胞中组成型活性 PKM1 同种型的表达导致乳酸产生减少，这种现象被称为 Warburg 效应中的 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，升高的 PKM2 活性通过谷氨酰胺分解增加 OAA 从头合成，从而抑制癌细胞中的 LDHA。我们还表明，用对 OAA 抑制具有相对抗性的兔 LDHA 替代人 LDHA，消除了 PKM2 活性升高与用 PKM2 激活剂处理的癌细胞中乳酸浓度降低之间的矛盾相关性。此外，与小鼠中人类 LDHA 表达肿瘤相比，兔 LDHA 表达肿瘤，显示对 PKM2 激活剂的抵抗力。这些发现通过显示 PKM2 激活后 OAA 积累并抑制 LDHA 来描述 PKM2 悖论的机制解释。