Cancer metabolism meets systems biology: Pyruvate kinase isoform PKM2 is a metabolic master regulator

Fabian V Filipp
Systems Biology and Cancer Metabolism, Program for Quantitative and Systems Biology, University of California Merced, 5200 North Lake Road, Merced, CA 95343, USA.
DOI: 10.4103/1477-3163.115423


Pyruvate kinase activity is controlled by a tightly woven regulatory network. The oncofetal isoform of pyruvate kinase (PKM2) is a master regulator of cancer metabolism. PKM2 engages in parallel, feed-forward, positive and negative feedback control contributing to cancer progression. Besides its metabolic role, non-metabolic functions of PKM2 as protein kinase and transcriptional coactivator for c-MYC and hypoxia-inducible factor 1-alpha are essential for epidermal growth factor receptor activation-induced tumorigenesis. These biochemical activities are controlled by a shift in the oligomeric state of PKM2 that includes acetylation, oxidation, phosphorylation, prolyl hydroxylation and sumoylation. Metabolically active PKM2 tetramer is allosterically regulated and responds to nutritional and stress signals. Metabolically inactive PKM2 dimer is imported into the nucleus and can function as protein kinase stimulating transcription. A systems biology approach to PKM2 at the genome, transcriptome, proteome, metabolome and fluxome level reveals how differences in biomolecular structure translate into a global rewiring of cancer metabolism. Cancer systems biology takes us beyond the Warburg effect, opening unprecedented therapeutic opportunities.

Keywords: Cancer metabolism, catenin, control, epidermal growth factor receptor, feed-forward, feedback, fructose-1,6-bisphosphate, fructose-1,6-bisphosphatase, glutamic-oxalacetic transaminase, glutaminase, hypoxia-inducible factor 1-alpha, isoform, metabolomics, MYC, NMR, omics, pyruvate dehydrogenase, pyruvate dehydrogenase kinase, PKM1, PKM2, pyruvate kinase M2, pyruvate kinase, succinylaminoimidazolecarboxamide ribose-5-phosphate, seven in absentia homolog 2, serine, serine/arginine-rich splicing factor 3, signal transducer and activator of transcription 3, systems biology, Warburg