The Warburg effect in cancer cells is characterised by preferential aerobic glycolysis even in the presence of oxygen. Which enzyme's upregulation is primarily responsible for the shift to lactate production rather than pyruvate entering the TCA cycle?
- A Pyruvate dehydrogenase kinase 1 (PDK1) — phosphorylating and inactivating pyruvate dehydrogenase ✓
- B Pyruvate carboxylase — diverting pyruvate to oxaloacetate
- C Pyruvate kinase M2 (PKM2) — slowing glycolysis to allow biosynthetic intermediate diversion, with LDH-A converting pyruvate to lactate
- D Hexokinase II — overexpressed at outer mitochondrial membrane, trapping glucose-6-phosphate
Explanation
While multiple mechanisms contribute to the Warburg effect, PDK1 (pyruvate dehydrogenase kinase 1) is a key driver: it phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC), blocking conversion of pyruvate to acetyl-CoA and thereby preventing pyruvate entry into the TCA cycle. HIF-1α (activated in hypoxic tumour microenvironment even normoxically) transcriptionally upregulates PDK1 and LDH-A. PKM2 also plays a role by generating less pyruvate kinase activity (dimer form) allowing diversion of glycolytic intermediates to biosynthesis, with LDH-A completing the conversion to lactate.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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