title: Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2.
abstract: BACKGROUND
  Insulin 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin's role in cancer.
authors.affiliation: National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Mohd Askandar
authors.initials: MA
authors.lastname: Iqbal
authors.forename: Farid Ahmad
authors.initials: FA
authors.lastname: Siddiqui
authors.forename: Vibhor
authors.initials: V
authors.lastname: Gupta
authors.forename: Shilpi
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Prakasam
authors.initials: P
authors.lastname: Gopinath
authors.forename: Bhupender
authors.initials: B
authors.lastname: Kumar
authors.forename: Siddharth
authors.initials: S
authors.lastname: Manvati
authors.forename: Noor
authors.initials: N
authors.lastname: Chaman
authors.forename: Rameshwar N K
authors.initials: RN
authors.lastname: Bamezai
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007527:Isoenzymes; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011770:Pyruvate Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D007527:Isoenzymes; D009249:NADP; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D011770:Pyruvate Kinase; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases