Flipping the Warburg Switch - What can we learn from cancer?

[AdamS]

I read an interesting comment on a thread yesterday where a member said that they believed the cure/solution to ME would probably come from someone we don't expect...a cancer researcher.

That got me thinking, in Cort's most recent article one of the researchers said that ME is most similar to cancer from a mitochondrial standpoint. I decided to do a bit of searching and came across this...

Flicking the Warburg Switch—Tyrosine Phosphorylation of Pyruvate Dehydrogenase Kinase Regulates Mitochondrial Activity in Cancer Cells

Figure 1.
Overview of the Metabolic Effect of Tyrosine Phosphorylation of PDHK1

(A) Pyruvate is generated from glucose by the glycolytic pathway. The last step of glycolysis is the conversion of phosphoenolpyruvate (PEP) to pyruvate by pyruvate kinase. The M2 isoform of pyruvate kinase (PKM2) can form highly active tetrameric complexes. Pyruvate dehydrogenase complex (PDC) is a multimeric enzyme complex that catalyzes the irreversible oxidative decarboxylation of pyruvate to generate Acetyl-CoA. Acetyl-CoA is oxidized by the tricarboxylic acid (TCA) cycle to generate NADH and FADH2, which is used by the mitochondrial electron transport chain (ETC), and ATP-synthase to generate cellular energy.

(B) Tyrosine phosphorylation of pyruvate dehydrogenase kinase 1 (PDHK1) by oncogenic tyrosine kinases (such as FGFR1, BCR-ABL, JAK2, and FLT3-ITD) increases its activity toward pyruvate dehydrogenase alpha 1 (PDHA1), a subunit of the PDC. Phosphorylation of PDHA1 by PDHK1 blocks the conversion of pyruvate to Acetyl-CoA, inhibits mitochondrial pyruvate metabolism and increases lactate secretion. Phosphorylation of PKM2 reduces glycolytic activity by converting the tetrameric form to a dimeric form with lower activity. Tyrosine phosphorylation of PKM2 and PDHK1 enhances cancer cell proliferation in hypoxia and promotes tumor growth. Inhibition of mitochondrial pyruvate metabolism may increase glutamate-dependent anapleurosis and promote reductive metabolism of α-ketoglutarate (α-KG) to supply citrate for lipid synthesis (red arrows). Abbreviations: Glucose-6-phosphate dehydrogenase (G6PD), phosphofructokinase 2 (PFK2), phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2), phosphoglycerate mutase (PGAM1), lactate dehydrogenase (LDHA), ATP-citrate lyase (ACLY), malic enzyme (ME), glutamate (Glu), pentose-5-phosphate (P5P).

Looks kinda familiar right? I wonder if there has already been a lot of work done out there that can help us solve ME faster.

Overall, this work emphasizes that cancer metabolism is not a static condition dictated by genetic background or environmental conditions. Instead, metabolic enzymes can flexibly respond to cellular signaling cascades. It also illustrates the intricate link between signaling networks and metabolic pathways in cancer cells.

This also gave me quite a bit of hope.