Abstract
Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Because of differential regulation of enzymatic activities, PKM2, but not PKM1, has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC overexpression in murine livers did not affect c-MYC-induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC-induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process. Cancer Res; 77(16); 4355-64. ©2017 AACR.
Highlights
Aberrant cellular metabolism is one of the hallmarks of cancer [1]
We found that enforced c-MYC expression consistently led to tumor formation in FVB/N mice obtained from Jackson Laboratory, whereas c-MYC injection failed to induce liver tumor formation or induced liver tumors with significant delay and decreased penetrance in many other strains tested
Several recent reports using pyruvate kinase M2 (PKM2) knockout demonstrating that PKM2 is dispensable for normal embryonic development and either mammary gland tumorigenesis induced by HER2 or spontaneous liver tumorigenesis [8, 24] have challenged this idea
Summary
Aberrant cellular metabolism is one of the hallmarks of cancer [1]. Increased glucose transport and metabolism are among the most prominent metabolic abnormalities observed in multiple tumors and cancer models [2, 3]. In part triggered by expression changes of genes encoding metabolic. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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