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

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...

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Published in:Cytokine (Philadelphia, Pa.) Pa.), 2011-04, Vol.54 (1), p.100-107
Main Authors: Tsubaki, Masanobu, Yamazoe, Yuzuru, Yanae, Masashi, Satou, Takao, Itoh, Tatsuki, Kaneko, Junichi, Kidera, Yasuhiro, Moriyama, Kenzo, Nishida, Shozo
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Akt
AKT protein
Angiogenesis
Angiogenic factor
Animals
biosynthesis
Cancer
Cell Line, Tumor
Cytokines
ERK
Extracellular signal-regulated kinase
Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors
Fibroblast growth factor 2
Fibroblast Growth Factor 2 - metabolism
Gene expression
Gene Expression Regulation, Enzymologic
Hepatocyte growth factor
Hepatocyte Growth Factor - metabolism
K-Ras protein
mevalonic acid
Mevalonic Acid - metabolism
Mice
Microenvironments
mitogen-activated protein kinase
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Neovascularization, Pathologic
Osteosarcoma
Osteosarcoma - metabolism
Osteosarcoma cells
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphorylation
Polyisoprenyl Phosphates - metabolism
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
pyrophosphates
Ras
Ras protein
ras Proteins - antagonists & inhibitors
secretion
Secretions
Signal transduction
Statin
statins
Transforming Growth Factor beta - metabolism
Transforming growth factor- beta
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
vascular endothelial growth factors
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Summary: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.
ISSN:1043-4666
1096-0023
DOI:10.1016/j.cyto.2011.01.005