BackgroundInsulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined.ResultsWe observed that insulin up-regulated PKM2 expression, through PI3K/mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth.ConclusionThe study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin’s role in cancer.

Background:We earlier reported novel mutations in PKM2 that reduce its activity. Results: These mutations promoted cancer features and tumor growth in a dominant negative manner. Conclusion: Impaired PKM2 activity due to mutations benefits cancer. Significance: This study provides the first evidence linking natural mutations in PKM2 with cancer.

Background: Pyruvate kinase plays a crucial role in tumor cell proliferation, however, its role in differentiation is relatively unelucidated. Results: PKM2 and PKR dependent metabolic switch toward energy production and nuclear translocation of PKM2 was observed during megakaryocyte differentiation. Conclusion: ERK2 controlled status of PK isoforms is essential for megakaryocytic differentiation. Significance: Metabolic shift impact the process of differentiation.

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