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

Elizabeth K. Wiese, Sadae Hitosugi, Sharon T. Loa, Annapoorna Sreedhar, Lindsey G. Andres-Beck, Kiran Kurmi, Yuan Ping Pang, Larry M. Karnitz, Wilson I. Gonsalves, Taro Hitosugi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)954-968
Number of pages15
JournalNature Metabolism
Volume3
Issue number7
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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