title: AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway.
abstract: The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) modulates cellular energy metabolism, and promotes mitochondrial proliferation and apoptosis. Previous studies have shown that AICAR has anticancer effects in various cancers, however the roles of AMPK and/or the effects of AICAR on osteosarcoma have not been reported. In the present study, we evaluated the effects of AICAR on tumor growth and mitochondrial apoptosis in human osteosarcoma both in vitro and in vivo. For in vitro experiments, two human osteosarcoma cell lines, MG63 and KHOS, were treated with AICAR, and the effects of AICAR on cell growth and mitochondrial apoptosis were assessed by WST assays, TUNEL staining, and immunoblot analyses. In vivo, human osteosarcoma-bearing mice were treated with AICAR, and the mitochondrial proliferation and apoptotic activity in treated tumors were assessed. In vitro experiments revealed that AICAR activated AMPK, inhibited cell growth, and induced mitochondrial apoptosis in both osteosarcoma cell lines. In vivo, AICAR significantly reduced osteosarcoma growth without apparent body weight loss and AICAR increased both mitochondrial proliferation and apoptotic activity in treated tumor tissues. AICAR showed anticancer effects in osteosarcoma cells through an AMPK-dependent peroxisome proliferator‑activated receptor-γ coactivator-1α (PGC-1α)/mitochondrial transcription factor A (TFAM)/mitochondrial pathway. The findings in this study strongly suggest that AICAR could be considered as a potent therapeutic agent for the treatment of human osteosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Morishita
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Teruya
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueha
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Minoda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Katayama
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takemori
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Fukase
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.affiliation: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akisue
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000096:biosynthesis* / Q000235:genetics; D012265:Ribonucleotides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012265:Ribonucleotides; C499631:TFAM protein, human; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide