title: Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity.
abstract: Osteosarcoma is the most common type of primary bone tumor, novel therapeutic agents for which are urgently needed. To identify such agents, we screened a panel of approved drugs with a mouse model of osteosarcoma. The screen identified simvastatin, which inhibited the proliferation and migration of osteosarcoma cells in vitro Simvastatin also induced apoptosis in osteosarcoma cells in a manner dependent on inhibition of the mevalonate biosynthetic pathway. It also disrupted the function of the small GTPase RhoA and induced activation of AMP-activated protein kinase (AMPK) and p38 MAPK, with AMPK functioning upstream of p38 MAPK. Inhibitors of AMPK or p38 MAPK attenuated the induction of apoptosis by simvastatin, whereas metformin enhanced this effect of simvastatin by further activation of AMPK. Although treatment with simvastatin alone did not inhibit osteosarcoma tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was enhanced further by metformin administration. Our findings suggest that simvastatin induces apoptosis in osteosarcoma cells via activation of AMPK and p38 MAPK, and that, in combination with other approaches, it holds therapeutic potential for osteosarcoma. Mol Cancer Ther; 16(1); 182-92. ©2016 AACR.
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.|Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.|Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo Japan.|Faculty of Science, Mansoura University, Mansoura, Egypt.
authors: Walied A
authors: WA
authors: Kamel
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Eiji
authors: E
authors: Sugihara
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Nobusue
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.|Department of Orthopedic surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Sayaka
authors: S
authors: Yamaguchi-Iwai
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Nobuyuki
authors: N
authors: Onishi
authors: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo Japan.
authors: Kenta
authors: K
authors: Maki
authors: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo Japan.
authors: Yumi
authors: Y
authors: Fukuchi
authors: Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Koichi
authors: K
authors: Matsuo
authors: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo Japan.
authors: Akihiro
authors: A
authors: Muto
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors: Hideyuki
authors: H
authors: Saya
authors: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. t-shimizu@hoshi.ac.jp.|Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo Japan.
authors: Takatsune
authors: T
authors: Shimizu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D008687:Metformin; D019821:Simvastatin; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein