Simvastatin-induced apoptosis in osteosarcoma cells: A key role of rhoa-ampk/p38 mapk signaling in antitumor activity

Walied A. Kamel, Eiji Sugihara, Hiroyuki Nobusue, Sayaka Yamaguchi-Iwai, Nobuyuki Onishi, Kenta Maki, Yumi Fukuchi, Koichi Matsuo, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu

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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.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

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Simvastatin
Osteosarcoma
AMP-Activated Protein Kinases
Apoptosis
p38 Mitogen-Activated Protein Kinases
Metformin
Mevalonic Acid
Fat-Restricted Diet
Monomeric GTP-Binding Proteins
Biosynthetic Pathways
Cell Movement
Therapeutics
Bone and Bones
Growth
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Simvastatin-induced apoptosis in osteosarcoma cells : A key role of rhoa-ampk/p38 mapk signaling in antitumor activity. / Kamel, Walied A.; Sugihara, Eiji; Nobusue, Hiroyuki; Yamaguchi-Iwai, Sayaka; Onishi, Nobuyuki; Maki, Kenta; Fukuchi, Yumi; Matsuo, Koichi; Muto, Akihiro; Saya, Hideyuki; Shimizu, Takatsune.

In: Molecular Cancer Therapeutics, Vol. 16, No. 1, 01.01.2017, p. 182-192.

Research output: Contribution to journalArticle

Kamel, WA, Sugihara, E, Nobusue, H, Yamaguchi-Iwai, S, Onishi, N, Maki, K, Fukuchi, Y, Matsuo, K, Muto, A, Saya, H & Shimizu, T 2017, 'Simvastatin-induced apoptosis in osteosarcoma cells: A key role of rhoa-ampk/p38 mapk signaling in antitumor activity', Molecular Cancer Therapeutics, vol. 16, no. 1, pp. 182-192. https://doi.org/10.1158/1535-7163.MCT-16-0499
Kamel, Walied A. ; Sugihara, Eiji ; Nobusue, Hiroyuki ; Yamaguchi-Iwai, Sayaka ; Onishi, Nobuyuki ; Maki, Kenta ; Fukuchi, Yumi ; Matsuo, Koichi ; Muto, Akihiro ; Saya, Hideyuki ; Shimizu, Takatsune. / Simvastatin-induced apoptosis in osteosarcoma cells : A key role of rhoa-ampk/p38 mapk signaling in antitumor activity. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 1. pp. 182-192.
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