Abstract
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.
Highlights
Insulin is tightly associated with cancer progression; mechanistic insights into such observations are poorly understood
Insulin upregulates pyruvate kinase M2 (PKM2) expression in a PI3K/Mammalian target of rapamycin (mTOR) dependent manner by inducing HIF1α expression To examine the effect of insulin on PKM2 expression, serum starved HepG2 cells were treated with insulin for
Dose dependent effect of insulin on PKM2 expression revealed that 1 nM insulin substantially induced PKM2 expression, maximum increase in PKM2 expression was observed with 100 nM insulin for 8 hours (Figure 2B); suggesting to choose 100 nM insulin for further experiments
Summary
Insulin is tightly associated with cancer progression; mechanistic insights into such observations are poorly understood. 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. Aerobic glycolysis is believed to provide cancer cells a selective advantage to grow in Activity of PKM2 is critical to determine a shift in metabolism required for tumor growth. Decreased PKM2 activity is believed to favour rapidly proliferating cancer cells; the phenomenology of PKM2 activity regulation by external factors is not well understood. PKM2 exists in highly active (tetramer) and less active (dimer/monomer) oligomeric forms. Disruption of active PKM2 tetramers results in accumulation of less active PKM2 monomers/dimers, promoting anabolic synthesis [9,13]. Our previous work has shown how two missense mutations in PKM2 stabilized less active PKM2 form to promote cellular growth and polyploidy [16]
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