title: Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation.
abstract: Tumor cells express the glycolytic regulator pyruvate kinase subtype M2 (M2-PK), which can occur in a tetrameric form with high affinity to its substrate phosphoenolpyruvate (PEP) and a dimeric form with a low PEP affinity. The transition between both conformations contributes to the control of glycolysis and is important for tumor cell proliferation and survival. Here we targeted M2-PK by synthetic peptide aptamers, which specifically bind to M2-PK and shift the isoenzyme into its low affinity dimeric conformation. The aptamer-induced dimerization and inactivation of M2-PK led to a significant decrease in the PK mass-action ratio as well as ATP:ADP ratio in the target cells. Furthermore, the expression of M2-PK-binding peptide aptamers moderately reduced the growth of immortalized NIH3T3 cell populations by decelerating cell proliferation, but without affecting apoptotic cell death. Moreover, the M2-PK-binding peptide aptamers also reduced the proliferation rate of human U-2 OS osteosarcoma cells. In the present study, we developed the first specific inhibitors of the pyruvate kinase isoenzyme type M2 and present evidence that these inhibitors moderately decelerate tumor cell proliferation.
authors.affiliation: Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria.|Tumorvirology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gilles A
authors.initials: GA
authors.lastname: Spoden
authors.affiliation: Department for Biochemistry and Endocrinology, Veterinary Faculty, University of Giessen, Giessen, Germany.|ScheBo Biotech AG, Netanyastrasse 3, Giessen, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Mazurek
authors.affiliation: Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria.|Tumorvirology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Morandell
authors.affiliation: Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bacher
authors.affiliation: Department of Pediatrics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ausserlechner
authors.affiliation: Department for Molecular and Cellular Biology, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria.|Molecular Oncology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Austria.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
authors.affiliation: Department for Biochemistry and Endocrinology, Veterinary Faculty, University of Giessen, Giessen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Eigenbrodt
authors.affiliation: Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Innsbruck, Austria.|Tumorvirology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Zwerschke
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052158:Aptamers, Peptide / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006019:Glycolysis; D006801:Humans; D007525:Isoelectric Focusing; D007536:Isomerism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010957:Plasmids; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D052158:Aptamers, Peptide; D047428:Protein Kinase Inhibitors; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase