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

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

doi:10.3892/ijo.2016.3775

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

Authors:
- Masayuki Morishita
- Teruya Kawamoto
- Hitomi Hara
- Yasuo Onishi
- Takeshi Ueha
- Masaya Minoda
- Etsuko Katayama
- Toshiyuki Takemori
- Naomasa Fukase
- Masahiro Kurosaka
- Ryosuke Kuroda
- Toshihiro Akisue
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Affiliations: Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Published online on: November 21, 2016 https://doi.org/10.3892/ijo.2016.3775
Pages: 23-30
Copyright: © Morishita et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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