title: The antioxidant uncoupling protein 2 stimulates hnRNPA2/B1, GLUT1 and PKM2 expression and sensitizes pancreas cancer cells to glycolysis inhibition.
abstract: 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.
authors.affiliation: Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brandi
authors.affiliation: Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cecconi
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cordani
authors.affiliation: Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute (ISCIII), Madrid, Spain; Palma Institute for Health Research (IdISPa), E07010 Palma, Spain; Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma, Spain.
authors.forename: Margalida
authors.initials: M
authors.lastname: Torrens-Mas
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Pacchiana
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Dalla Pozza
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Butera
authors.affiliation: Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy; ISALIT, Novara, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Manfredi
authors.affiliation: Department of Sciences and Technological Innovation, University of Eastern Piedmont, Alessandria, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Marengo
authors.affiliation: Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute (ISCIII), Madrid, Spain; Palma Institute for Health Research (IdISPa), E07010 Palma, Spain; Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Oliver
authors.affiliation: Physiopathology of Obesity and Nutrition, CIBERobn (CB06/03), Carlos III Health Research Institute (ISCIII), Madrid, Spain; Palma Institute for Health Research (IdISPa), E07010 Palma, Spain; Multidisciplinar Group of Translational Oncology, University Research Institute on Health Sciences (IUNICS), University of the Balearic Islands, E07122 Palma, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Roca
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: ilaria.dando@univr.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dando
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: massimo.donadelli@univr.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Donadelli
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D039823:Iridoids / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000235:genetics* / Q000378:metabolism; D000071246:Uncoupling Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000111:Acetylcysteine; D002352:Carrier Proteins; D003847:Deoxyglucose; D051272:Glucose Transporter Type 1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D039823:Iridoids; D007770:L-Lactate Dehydrogenase; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013963:Thyroid Hormones; D000071246:Uncoupling Protein 2; D000097810:Thyroid Hormone-Binding Proteins; C103749:HNRNPAB protein, human; C495677:SLC2A1 protein, human; C000604389:UCP2 protein, human; C007834:genipin
keywords: Cancer; Metabolism; Proteomics; UCP2; Uncoupling proteins; Warburg effect