The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

  title={The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth},
  author={Heather R. Christofk and Matthew G. Vander Heiden and Marian H Harris and Arvind Ramanathan and Robert E. Gerszten and Ru Wei and Mark D. Fleming and Stuart L. Schreiber and Lewis C. Cantley},
Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is… 
M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth
Although pyruvate kinase knockdown results in modest impairment of proliferation in vitro, in vivo growth of established xenograft tumors is unaffected by PKM2 absence, suggesting that other metabolic pathways bypass its function.
Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.
  • S. Mazurek
  • Biology, Computer Science
    The international journal of biochemistry & cell biology
  • 2011
Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells
Induction of PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage.
Influence of Pyruvate Kinase Isoform Expression on Primary Cell Proliferation and Metabolism
The data suggest that in comparison to PKM1, PKM2 expression promotes anabolism in proliferating cells by favoring metabolic flux that supports nucleotide biosynthetic pathways and increases flux to the TCA cycle.
Identification of small molecule inhibitors of pyruvate kinase M2.
PKM2 functions as a histone kinase
The recent studies demonstrated that activation of epidermal growth factor (EGF) receptor (EGFR) results in translocation of PKM2, but not PKM1, into the nucleus in glioblastoma cells, breast cancer cells and prostate cancer cells, a phenomenon discovered by Otto Warburg in 1924 and known as the Warburg effect or aerobic glycolysis.
Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis
The role of pyruvate kinase M2 in normal cells vs. cancerous cells and its regulation at the transcriptional level is highlighted and the role of PKM2 as a potential diagnostic marker and as a therapeutic target in cancer treatment is highlighted.
Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth
The findings suggest that tyrosine phosphorylation regulates PKM2 to provide a metabolic advantage to tumor cells, thereby promoting tumor growth.
Tyrosine Kinase Signaling in Cancer Metabolism: PKM2 Paradox in the Warburg Effect
Recent advances revealing the importance of tyrosine kinases in the regulation of the Warburg Effect as well as the role of PKM2 in the promotion of tumor growth are summarized.


Pyruvate kinase M2 is a phosphotyrosine-binding protein
The results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells and Diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors.
Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death.
The results show that the tumor marker PKM2 plays a general role in caspase-independent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development.
Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis.
Significant structural differences among the human M2, rabbit muscle M1, and the human R isozymes are observed, especially in the orientation of the FBP-activating loop, which is in a closed conformation when FBP is bound.
Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis
Transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools, and glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
Ras transformation requires metabolic control by 6-phosphofructo-2-kinase
Data indicate that the PFKFB3 protein product may serve as an essential downstream metabolic mediator of oncogenic ras, and it is proposed that pharmacologic inhibition of this enzyme should selectively suppress the high rate of glycolysis and growth by cancer cells.
Why do cancers have high aerobic glycolysis?
It is proposed that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Growth Factors Can Influence Cell Growth and Survival through Effects on Glucose Metabolism
It is suggested that a primary function of growth factors is to regulate glucose uptake and metabolism and thus maintain mitochondrial homeostasis and enable anabolic pathways required for cell growth.