title: Regulation of the expression and activity of glucose and lactic acid metabolism-related genes by protein kinase C in skeletal muscle cells.
abstract: Protein kinase C (PKC) modulators are very attractive therapeutic targets in cancer. Since most cancer cells display increased glycolysis, elucidations of the effects of PKC activation on glycolysis is necessary for the development of effective medicine. In the present study, to clarify the role of PKC in the regulation of glycolysis, we examined the effect of phorbol 12-myristate 13-acetate (PMA), a PKC activator, on the expression and activity of glucose and lactic acid metabolism-related genes in human rhabdomyosarcoma cells (RD cells). In parallel to increases in glucose uptake and mRNA levels of glucose transporters (GLUTs) induced by PMA treatment for 6 h, the hexokinase (HK) mRNA level and activity were also significantly increased in RD cells. On the other hand, a significant increase in lactate dehydrogenase (LDH) mRNA level and activity was seen when the cells were incubated with PMA for 24 h, but not for 6 or 12 h, and was associated with lactic acid production. These effects by PMA treatment were markedly suppressed by Bisindolylmaleimide (BIM), a PKC inhibitor. Furthermore, chetomin, a hypoxia-inducible factor 1 (HIF-1) inhibitor, completely abrogated the increment of LDH mRNA level and activity as well as monocarboxylate transporter (MCT) 4, a lactic acid efflux transporter. In conclusion, we found that HK and LDH activity induced by PKC activation was associated with the glucose uptake and lactic acid level and that LDH and MCT4 are modulated by a common factor, HIF-1.
authors.affiliation: Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University.
authors.forename: Sho
authors.initials: S
authors.lastname: Otake
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Narumi
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yurika
authors.initials: Y
authors.lastname: Kikutani
authors.forename: Ayako
authors.initials: A
authors.lastname: Furugen
authors.forename: Meguho
authors.initials: M
authors.lastname: Watanabe
authors.forename: Natsuko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D045744:Cell Line, Tumor; D004220:Disulfides / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D006593:Hexokinase / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000235:genetics; D019344:Lactic Acid / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D004220:Disulfides; D051246:Glucose Transport Proteins, Facilitative; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D012333:RNA, Messenger; C406962:SLC16A4 protein, human; C001598:chetomin; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D006593:Hexokinase; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate