The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition

Free Radic Biol Med. 2016 Dec;101:305-316. doi: 10.1016/j.freeradbiomed.2016.10.499. Epub 2016 Oct 27.


Several evidence indicate that metabolic alterations play a pivotal role in cancer development. Here, we report that the mitochondrial uncoupling protein 2 (UCP2) sustains the metabolic shift from mitochondrial oxidative phosphorylation (mtOXPHOS) to glycolysis in pancreas cancer cells. Indeed, we show that UCP2 sensitizes pancreas cancer cells to the treatment with the glycolytic inhibitor 2-deoxy-D-glucose. Through a bidimensional electrophoresis analysis, we identify 19 protein species differentially expressed after treatment with the UCP2 inhibitor genipin and, by bioinformatic analyses, we show that these proteins are mainly involved in metabolic processes. In particular, we demonstrate that the antioxidant UCP2 induces the expression of hnRNPA2/B1, which is involved in the regulation of both GLUT1 and PKM2 mRNAs, and of lactate dehydrogenase (LDH) increasing the secretion of L-lactic acid. We further demonstrate that the radical scavenger N-acetyl-L-cysteine reverts hnRNPA2/B1 and PKM2 inhibition by genipin indicating a role for reactive oxygen species in the metabolic reprogramming of cancer cells mediated by UCP2. We also observe an UCP2-dependent decrease in mtOXPHOS complex I (NADH dehydrogenase), complex IV (cytochrome c oxidase), complex V (ATPase) and in mitochondrial oxygen consumption, suggesting a role for UCP2 in the counteraction of pancreatic cancer cellular respiration. All these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation with the concomitant metabolic shift from mtOXPHOS to the glycolytic pathway.

Keywords: Cancer; Metabolism; Proteomics; UCP2; Uncoupling proteins; Warburg effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Deoxyglucose / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Glucose Transporter Type 1 / genetics*
  • Glucose Transporter Type 1 / metabolism
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics*
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Iridoids / pharmacology
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidative Phosphorylation / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Thyroid Hormones / genetics*
  • Thyroid Hormones / metabolism
  • Uncoupling Protein 2 / antagonists & inhibitors
  • Uncoupling Protein 2 / genetics*
  • Uncoupling Protein 2 / metabolism


  • Carrier Proteins
  • Glucose Transporter Type 1
  • HNRNPAB protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Iridoids
  • Membrane Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • SLC2A1 protein, human
  • Thyroid Hormones
  • UCP2 protein, human
  • Uncoupling Protein 2
  • thyroid hormone-binding proteins
  • Deoxyglucose
  • genipin
  • L-Lactate Dehydrogenase
  • Acetylcysteine