title: Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity.
abstract: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used cholesterol-lowering agents for prevention of obstructive cardiovascular events. However, statins can cause a variety of skeletal muscle problems, and exercise leads to an increase in statin-induced muscle injury. Exercise induces the protein content of monocarboxylate transporter 4 (MCT4), which is expressed strongly in skeletal muscle and is thought to play a major role in the transport of metabolically important monocarboxylates such as l-lactate. We previously reported that α-cyano-4-hydroxycinnamate, an MCT4 inhibitor, increased the inhibition of growth of RD cells, a prototypic embryonal rhabdomyosarcoma cell line (an RD cell line), as a model of in vitro skeletal muscle, induced by a statin. However, it is unclear whether statin-induced RD cell cytotoxicity is associated with MCT4 expression. We, therefore, examined the relationship between statin-induced cytotoxicity and MCT4 expression in RD cells. Atorvastatin reduced the number of viable cells and upregulated MCT4, but not MCT1, mRNA level in a concentration-dependent manner. MCT4 knockdown suppressed atorvastatin-, simvastatin-, and fluvastatin-induced reduction of cell viability and apoptosis compared with negative control-treated cells. In this study, we demonstrated that MCT4 expression is associated with statin-induced cytotoxicity.
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Kikutani
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Konishi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Narumi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Furugen
authors.affiliation: Hokkaido Pharmaceutical University School of Pharmacy, Sapporo 006-8590, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo 060-8648, Japan. Electronic address: ken-i@pharm.hokudai.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000069059:Atorvastatin / Q000009:adverse effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D015870:Gene Expression; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D027501:Monocarboxylic Acid Transporters / Q000032:analysis / Q000235:genetics*; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D034741:RNA, Small Interfering; C406962:SLC16A4 protein, human; D000069059:Atorvastatin
keywords: cytotoxicity; monocarboxylate transporter 4; statin