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.
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The accession codes used in this study are 6MV8 (hLDHA) and 5NQB (rbLDHA) from the PDB. Supplementary Information including Supplementary Fig. 1 exemplifying the gating strategy for Extended Data Fig. 4d are provided with this paper. Source data are provided with this paper.
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Acknowledgements
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.
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E.K.W., S.H., S.T.L., A.S. and T.H. performed the experiments and analysed the data with input from K.K. and L.M.K. L.G.A.-B. assisted with SBFSEM data analysis. Y.-P.P. performed the computational work. W.I.G. provided critical reagents and patient samples. E.K.W. and T.H. wrote the paper. All authors contributed to discussion about the data.
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Extended data
Extended Data Fig. 1 Increased PKM2 activity decreases LDH activity and lactate concentration. Related to Fig. 1.
a. Pyruvate kinase activity from lysates of PKM2 or PKM1-expressing H1299 cells. Corresponding western blots of H1299 vector, PKM2, and PKM1 cell lysates with antibodies against PKM, PKM2, PKM1, LDHA, and β-actin. b. Whole cell lactate concentrations of PKM2 and PKM1 expressing H1299 cells. c. Relative lactate production rate in PKM2 and PKM1 expressing H1299 cells. d. Relative lactate production rate in RPMI 8226 cells treated with vehicle or DASA. e. Pyruvate concentrations in PKM2 or PKM1 expressing H1299 cells. f-g. Relative glucose uptake of H1299 (f) and RPMI 8226 (g) cells with vehicle or DASA treatment. h. 13C lactate labelling rate of RPMI 8226 cells incubated with 13C6 glucose and vehicle or 40 μM DASA. i. 13C pyruvate labeling rate of RPMI 8226 cells incubated with 13C6 glucose and vehicle or 40 μM DASA. j. In situ LDH activity in RPMI 8226 cells with vehicle or DASA treatment. k. 13C lactate labeling rate of PKM2 and PKM1 expressing H1299 cells incubated with 13C6 glucose. l. 13C pyruvate labeling rate of PKM2 and PKM1 expressing H1299 cells incubated with 13C6 glucose. m. In situ LDH activity in PKM2 and PKM1 expressing H1299 cells. n. LDH activity from lysates of RPMI 8226 cells treated with 40 μM DASA or vehicle overnight. Below, the corresponding western blots of the RPMI 8226 lysates with antibodies against LDHA, LDHB, and β-actin. o. LDH activity from lysates of H1299 cells expressing PKM2 or PKM1. Below, the corresponding western blots of the PKM2 and PKM1 expressing H1299 lysates with antibodies against LDHA, LDHB, and β-actin. Data is represented as the mean and error bars represent the standard deviation from n = 3 for (a), (k), (l), (m), n = 4 for (b), (c), (d), (e), (f), (g), (h), (i), (j), n = 6 for (n), n = 7 for (o) of biologically independent replicates. Western blot results in (a), (n), (o) are representative experiments of 3 biologically independent replicates. P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 2 OAA is a competitive inhibitor of hLDHA. Related to Fig. 2.
a. Gas chromatogram of malate 3-TMS derivative (m/z 335) of pure malate standard (top). Gas chromatogram of malate 3-TMS derivative (m/z 335) of an in vitro LDH activity assay sample in which purified recombinant hLDHA was incubated with OAA (bottom). No malate was detected. b. Relative LDHA activity in the presence of various metabolites, determined using purified recombinant human LDHA and a fluorescence based LDH activity assay. c. Fluorescence intensity scan at ex. 280 nm of purified human LDHA incubated with increasing concentrations of OAA. Data is represented as the mean and error bars represent the standard deviation from n = 4 for (b) of independent replicates in vitro. Chromatograms in (a) and fluorescence curves in (c) are representative experiments of three independent replicates in vitro and the P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 3 GC–MS detection of OAA 3-TBDMS and analysis of glucose uptake.
a. (left) Scan of m/z 417 of pure 12C OAA standard derivatized with DMF-MTBSTFA. (middle) Mass spectrum of pure 12C OAA standard, derivatized with DMF-MTBSTFA. m/z 417 corresponds to OAA 3-TBDMS M-57 fragment. (right) Standard curve showing a positive, linear relationship between OAA amount and m/z 417 peak intensity of pure OAA standard. b. (left) Scan of m/z 417 of H1299 cellular metabolites labelled with 13C glucose, extracted with 1:1 methanol:water containing 5 mM ninhydrin, with or without 12C OAA spike. (middle) Isotopomer distribution of OAA (m/z 417) from H1299 cellular metabolites labeled with 13C glucose, extracted with 1:1 methanol:water containing 5 mM ninhydrin, with or without 12C OAA spike. (right) Ion abundance, normalized using IsoPat2, of isotopomer distribution data from (middle). c. Relative glucose uptake of H1299 (left) and RPMI 8226 (right) cells treated with vehicle or 1 mM diethyl-ester OAA. d. Relative glucose uptake of H1299 (left) and RPMI 8226 (right) cells treated with vehicle or 10 mM aspartate. Data is represented as the mean and error bars represent the standard deviation from n = 4 for (c), (d) of biologically independent replicates. Results in (a) are representative experiments of three independent replicates in vitro. Results in (b) are representative experiments of 3 biologically independent replicates. P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 4 Activation of PKM2 increases cellular OAA concentrations to inhibit LDH activity. Related to Fig. 4.
a. Relative whole cell OAA concentrations of RPMI 8226 cells treated with 40 μM DASA or vehicle overnight. Whole cell metabolites were extracted with 1:1 methanol:water containing 5 mM ninhydrin, with or without 12C OAA spike, derivatized, and analysed with GC-MS. b. Relative whole cell OAA concentrations of PKM2 and PKM1 expressing H1299 cells. c. Schematic of fractionation method. d. Relative mean signal intensity, determined by flow cytometry, of (left) ER-BODIPY red, (middle) Golgi tracker red, and (right) Mito tracker red stained H1299 cells, treated with 40 μM DASA or vehicle. e. Representative serial block face scanning electron microscopy (SBFSEM) image of an H1299 cell. Small organelles included in the small organelle fraction are colored blue. Representative golgi, endoplasmic reticulum (ER), and mitochondria are circled in white. Image is one slice from one representative cell. f. Whole cell volumes as well as fractionated volumes of 12 cells analysed using SBFSEM. g. Western blot of H1299 lysate and increasing concentrations of purified recombinant LDHA. Corresponding standard curve constructed from the average pixel density of each LDHA purified recombinant protein band and used to determine the amount of LDHA protein in H1299 lysate. h. In vitro LDHA activity assay, using purified recombinant LDHA and pyruvate and cytosolic OAA concentrations determined under 40 μM DASA or vehicle treatment in H1299 cells. LDHA activity was determined by analysing 13C1 lactate produced from 13C1 pyruvate by GC-MS. Western blot results are representative experiments of three independent replicates. Data is represented as the mean and error bars represent the standard deviation from n = 4 for (a), (b), (h), n = 3 for (d) of biologically independent replicates. Micrograph in (e) is a representative experiment of 12 biologically independent replicates. Standard curve in (g) is a representative experiment of 3 independent replicates in vitro. The western blot in (g) is a representative experiment of 3 biologically independent replicates. P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 5 PKM2 activity increases glutamine derived OAA. Related to Fig. 5.
a. Isotopomer analysis of 13C6 glucose-derived carbon incorporation to OAA in RPMI 8226 cells treated with 13C6 glucose and 40 μM DASA or vehicle overnight. b. Isotopomer analysis of 13C5 glutamine-derived carbon incorporation to OAA in RPMI 8226 cells treated with 13C5 glutamine and 40 μM DASA or vehicle overnight. c. Western blot analysis with antibodies against GPT2 and β-actin of H1299 lysates from cells treated with vehicle or 40 μM DASA overnight. d. Relative OAA concentrations in H1299 GPT2 knockdown cells treated with vehicle or 40 μM DASA overnight. e. Western blot analysis of H1299 vector and PHGDH knockdown cell lysates with antibodies against PHGDH and β-actin. f. 13C lactate labeling rate of H1299 vector and PHGDH knockdown cells incubated with 13C6 glucose and vehicle or 40 μM DASA. g. 13C pyruvate labeling rate of H1299 vector and PHGDH knockdown cells incubated with 13C6 glucose and vehicle or 40 μM DASA. h. In situ LDH activity in H1299 vector and PHGDH knockdown cells treated with vehicle or 40 μM DASA. i. Western blot analysis of H1299 vector and PC knockdown cell lysates with antibodies against PC and β-actin. j. 13C lactate labeling rate of H1299 vector and PC knockdown cells incubated with 13C6 glucose and vehicle or 40 μM DASA. k. 13C pyruvate labeling rate of H1299 vector and PC knockdown cells incubated with 13C6 glucose and vehicle or 40 μM DASA. l. In situ LDH activity in H1299 vector and PC knockdown cells treated with vehicle or 40 μM DASA. Data is represented as the mean and error bars represent the standard deviation from n = 4 for (a), (d), (f), (g), (h), (j), (k), (l), n = 3 for (b) of biologically independent replicates. Western blot results in (c), (e), (i) are representative experiments of 3 biologically independent replicates. P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 6 LDHB has a small effect on the total LDH activity in H1299 cells. Related to Fig. 6.
a. The IC50 of OAA against human LDHB determined using purified recombinant human LDHB and analysis of 13C1 lactate derived from 13C1 pyruvate. The IC50 was identified as 1,021 ± 86 μM. b. Western blot of H1299 lysate and increasing concentrations of purified recombinant LDHB. Corresponding standard curve constructed from the average pixel density of LDHB purified recombinant protein band and used to determine the amount of LDHB protein in H1299 lysate. c. LDH activity, determined using a fluorescence based LDH activity assay using diluted lysates from H1299 vector and LDHB knockdown cells. The corresponding western blots of the H1299 lysates used in the above activity assay with antibodies against LDHB and β-actin. Data is represented as the mean and error bars represent the standard deviation from n = 4 for (a), n = 3 for (c) of independent replicates in vitro. Standard curve in (b) is a representative experiment of 3 independent replicates in vitro. Western blots in (b) (c) are representative experiments of 3 biologically independent replicates. P values were determined by a two-tailed Student’s t-test.
Extended Data Fig. 7 OAA inhibition of LDHA increases the response to TEPP-46 in vivo.
a. Pyruvate kinase enzyme activity assay in lysates from H1299 cells treated with vehicle or 40 μM TEPP-46 overnight. The corresponding western blots of H1299 cell lysates with antibodies against PKM2 and β-actin. b. Isotopomer analysis of 13C5 glutamine-derived carbon incorporation to OAA in H1299 cells treated with 13C5 glutamine and 40 μM TEPP-46 or vehicle overnight. c. Ki67 staining of hLDHA- and rbLDHA-expressing H1299 tumours from mice treated with vehicle or TEPP-46. Ki67 staining results are representative experiments of 3 biologically independent replicates. Western blot results are representative experiments of 3 independent replicates. Data is represented as the mean and error bars represent the standard deviation from n = 3 for (a), (b) of biologically independent measurements. P values were determined by a two-tailed Student’s t-test.
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Wiese, E.K., Hitosugi, S., Loa, S.T. et al. Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect. Nat Metab 3, 954–968 (2021). https://doi.org/10.1038/s42255-021-00424-5
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DOI: https://doi.org/10.1038/s42255-021-00424-5
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