Morishita Masayuki, Kawamoto Teruya, Hara Hitomi, Onishi Yasuo, Ueha Takeshi, Minoda Masaya, Katayama Etsuko, Takemori Toshiyuki, Fukase Naomasa, Kurosaka Masahiro, Kuroda Ryosuke, Akisue Toshihiro
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.
Int J Oncol. 2017 Jan;50(1):23-30. doi: 10.3892/ijo.2016.3775. Epub 2016 Nov 21.
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.
AMP 激活的蛋白激酶（AMPK）激活剂 5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）可调节细胞能量代谢，并促进线粒体增殖和凋亡。先前的研究表明，AICAR 在多种癌症中具有抗癌作用，然而，AMPK 的作用和/或 AICAR 对骨肉瘤的影响尚未见报道。在本研究中，我们评估了 AICAR 对人骨肉瘤体外和体内肿瘤生长及线粒体凋亡的影响。对于体外实验，用 AICAR 处理两种人骨肉瘤细胞系 MG63 和 KHOS，并通过 WST 检测、TUNEL 染色和免疫印迹分析评估 AICAR 对细胞生长和线粒体凋亡的影响。在体内，用 AICAR 处理荷人骨肉瘤小鼠，并评估处理后肿瘤中的线粒体增殖和凋亡活性。体外实验显示，AICAR 激活 AMPK，抑制两种骨肉瘤细胞系的细胞生长，并诱导线粒体凋亡。在体内，AICAR 显著降低骨肉瘤生长，且无明显体重减轻，AICAR 增加处理后肿瘤组织中的线粒体增殖和凋亡活性。AICAR 通过 AMPK 依赖的过氧化物酶体增殖物激活受体γ 共激活因子 1α（PGC-1α）/线粒体转录因子 A（TFAM）/线粒体途径在骨肉瘤细胞中显示出抗癌作用。本研究结果强烈表明，AICAR 可被视为治疗人骨肉瘤的有效治疗剂。
