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Editorial
. 2019 Mar;8(Suppl 2):S156-S161.
doi: 10.21037/tcr.2018.12.31.

The time has come to pull renal cancer's sweet tooth

Adam Kinnaird  1   2 , Evangelos D Michelakis  1
Affiliations
Editorial

The time has come to pull renal cancer's sweet tooth

Adam Kinnaird et al. Transl Cancer Res. 2019 Mar.
No abstract available

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Conflict of interest statement

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.12.31). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The Warburg effect in ccRCC: a central role of mitochondrial PDC. (A) The metabolism of ccRCC is characterized by suppressed mitochondrial glucose oxidation and enhanced glycolysis due to upregulation of the enzyme pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase complex (PDC) and its conversion of pyruvate to acetyl-CoA production. Pyruvate, instead of producing acetyl-CoA to feed the Krebs’ cycle, is metabolized into lactate and contributes to the biosynthesis of amino acids, nucleotides and lipids for use in cell proliferation. The decreased flow of acetyl-CoA into the Krebs’ cycle reduces Krebs’ intermediates and electron donors delivered to the electron transport chain, leading to a hyperpolarized mitochondrial membrane potential. This hyperpolarization closes the voltage-gated mitochondrial transition pore (MTP), thereby trapping pro-apoptotic factors like cytochrome c (cyt c) and apoptosis inducing factor (AIF) inside the mitochondria, limiting apoptosis. (B) Inhibition of PDK by dichloroacetate (DCA) restores PDC activity and production of acetyl-CoA. This shunts glucose metabolism into the Krebs’ cycle, reducing lactate, amino acid and lipid production, as well as leading to a depolarization of the mitochondrial membrane and thus facilitating release of mitochondrial pro-apoptotic factors. ccRCC, clear cell renal cell cancer.
Figure 2
Figure 2
The Warburg effect is reversible in ccRCC. (A) Pyruvate dehydrogenase kinase 1 (PDK1) protein is expressed at high levels in ccRCC tumors but not in their adjacent normal kidney parenchyma in a patient undergoing radical nephrectomy (blue: DAPI, staining nuclei). (B) DCA reverses the Warburg effect, increasing production of acetyl-CoA, Krebs’ cycle intermediates including oxaloacetate, succinate, fumarate, and decreases the glycolytic products pyruvate and lactate. These data were generated by adding 13C-Glucose in the culture media of ccRCC cells and detecting the levels of labelled metabolites using mass spectroscopy, in a manner similar to the Courtney et al. paper (17). DCA also increased oxygen consumption (i.e., mitochondrial respiration) in ccRCC cells. (C) PDK-dependent phosphorylation of the PDC (in Serine 293) is inhibited by treatment with DCA in ccRCC cells. In an in vivo model with rodent ccRCC xenografts, oral DCA treatment reduced tumor growth. *, P<0.05. This figure is modified with permission from Kinnaird et al. 2016 (16). ccRCC, clear cell renal cell cancer; DCA, dichloroacetate; PDC, pyruvate dehydrogenase complex.
See this image and copyright information in PMC

Comment on

References

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