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|Walied A Kamel, Eiji Sugihara, Sayaka Yamaguchi,Koichi Matsuo, Akihiro Muto, Hideyuki Saya, Takatsune Shimizu|
|Keio University, Japan|
|ScientificTracks Abstracts: Oncol Cancer Case Rep|
|Osteosarcoma (OS) is the most common, non-hematopoietic, primary malignant bone tumor. Previously, we developed an OS mouse model by overexpressing c-MYC in bone marrow stromal cells derived from Ink4a/Arf knockout mice. We isolated highly tumorigenic cells (designated AXT cells) from tumors after serial transplantation. To obtain the novel candidate agents for OS, we performed drug screening and found that statins strongly suppressed AXT cell growth. Simvastatin treatment inhibited cell proliferation and induced apoptosis, which was almost fully rescued by the supplement of mevalonate and geranylgeranyl pyrophosphate but modestly by farnesyl pyrophosphate, suggesting that protein geranylgeranylation has a greater impact on OS cell viability. Simvastatin treatment inactivated RhoA through translocation of RhoA from membrane to cytosol and RhoA-GTP was accumulated by disruption of the interaction between RhoA and Rho-GDI. As a downstream signaling of RhoA, AMPK-p38MAPK pathway was strongly activated by simvastatin treatment, with AMPK functioning as an upstream effector of p38MAPK. Inhibition of AMPK or p38MAPK activation rescued apoptosis induced by simvastatin treatment, indicating that simvastatin exerts antitumor activity in OS via activation of AMPK- p38 MAPK pathway. Although treatment with simvastatin alone did not inhibit OS tumor growth in vivo, its combination with a fat-free diet induced a significant antitumor effect that was further enhanced by metformin administration. These findings suggest that the activation of AMPK- p38 MAPK pathway by statins become a potential therapeutic option for OS.|
Walied kamel, 32 years old, a PHD student at keio unviersity, school of medicine, Tokyo, Japan.
Email: [email protected]
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