title: Blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathways by statins reduces the expression of bFGF, HGF, and TGF-β as angiogenic factors in mouse osteosarcoma.
abstract: The tumor microenvironment plays a critical role in modulating malignant behavior and can dramatically influence cancer treatment strategies. We investigated whether statins inhibit the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor-β (TGF-β) mRNA in the mouse osteosarcoma cell line LM8. We found that statins significantly inhibited mRNA expressions of bFGF, HGF, and TGF-β, and bFGF, HGF, and TGF-β secretions at concentrations that did not have antiproliferative effects on LM8 cells, but had no effect on the mRNA expression and secretion of VEGF. The inhibition of bFGF, HGF, and TGF-β mRNA expression, and bFGF, HGF, TGF-β secretions was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination with statins. Furthermore, statins reduced the membrane localization of K-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our research indicates that statins inhibit GGPP biosynthesis in the mevalonate pathway, and then inhibit signal transduction in the Ras/ERK and Ras/Akt pathways, thereby inhibiting bFGF, HGF, TGF-β expression in LM8 cells. These results suggest that statins are potentially useful as anti-angiogenic agents for the treatment of osteosarcoma.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanae
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.forename: Junichi
authors.initials: J
authors.lastname: Kaneko
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kidera
authors.forename: Kenzo
authors.initials: K
authors.lastname: Moriyama
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic; D012516:Osteosarcoma / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D011106:Polyisoprenyl Phosphates; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid