TY - JOUR
T1 - Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect
AU - Wiese, Elizabeth K.
AU - Hitosugi, Sadae
AU - Loa, Sharon T.
AU - Sreedhar, Annapoorna
AU - Andres-Beck, Lindsey G.
AU - Kurmi, Kiran
AU - Pang, Yuan Ping
AU - Karnitz, Larry M.
AU - Gonsalves, Wilson I.
AU - Hitosugi, Taro
N1 - Funding Information:
We thank the Mayo Microscopy and Cell Analysis Core and the Mayo Pathology Research Core at Mayo Clinic Rochester for experimental and technical support. We thank J. Maher and S. Kaufmann for their critical reading of the paper. This research was supported in part by National Institutes of Health (NIH) grant no. R01 CA225680 (T.H.), Research Scholar grant (no. RSG-19-076-01-TBE) from the American Cancer Society (T.H.), the Eagles Cancer Research Fund (T.H.), a Team Science Platform Award from the Mayo Clinic Center for Biomedical Discovery (T.H.), the Developmental Therapeutics Program from the Mayo Clinic Cancer Center (T.H.) and the Mayo Clinic Breast SPORE grant no. P50 CA116201 (T.H.). W.I.G. was supported by the National Cancer Institute of the NIH under award no. K23 CA218742. S.T.L. was supported by NIH grant no. R25 GM075148-14. E.K.W. was supported by NIH grant no. T32 GM072474 and a predoctoral fellowship from the Mayo Foundation for Education and Research.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s42255-021-00424-5
DO - 10.1038/s42255-021-00424-5
M3 - Article
C2 - 34226744
AN - SCOPUS:85109938316
VL - 3
SP - 954
EP - 968
JO - Nature Metabolism
JF - Nature Metabolism
SN - 2522-5812
IS - 7
ER -