AICAR induces mitochondrial apoptosis in human osteosarcoma cells through an AMPK-dependent pathway

作者：Morishita Masayuki; Kawamoto Teruya^*; Hara Hitomi; Onishi Yasuo; Ueha Takeshi; Minoda Masaya; Katayama Etsuko; Takemori Toshiyuki; Fukase Naomasa; Kurosaka Masahiro; Kuroda Ryosuke; Akisue Toshihiro

来源：International Journal of Oncology, 2017, 50(1): 23-30.

DOI：10.3892/ijo.2016.3775

• osteosarcoma
• AMP-activated protein kinase
• 5-aminoimidazole-4-carboxiamide ribonucleotide
• mitochondria
• peroxisome proliferator-activated receptor-gamma coactivator-1 alpha
• mitochondrial transcription factor A

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-gamma coactivator-1 alpha (PGC-1 alpha)/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.

• 出版日期2017-1