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

被引：101

作者：

Tsubaki, Masanobu ^{[1
]}

Yamazoe, Yuzuru ^{[1
,2
]}

Yanae, Masashi ^{[1
,3
]}

Satou, Takao ^{[4
]}

Itoh, Tatsuki ^{[4
]}

Kaneko, Junichi ^{[1
]}

Kidera, Yasuhiro ^{[1
,2
]}

Moriyama, Kenzo ^{[2
]}

Nishida, Shozo ^{[1
]}

机构：

[1] Kinki Univ, Sch Pharm, Div Pharmacotherapy, Higashiosaka, Osaka 5778502, Japan

[2] Kinki Univ Hosp, Dept Pharm, Osaka 5898511, Japan

[3] Kinki Univ, Sch Med, Sakai Hosp, Dept Pharm, Osaka 5900132, Japan

[4] Kinki Univ, Sch Med, Dept Pathol, Osaka 5898511, Japan

来源：

CYTOKINE | 2011年 / 54卷 / 01期

关键词：

Statin; Ras; ERK; Akt; Angiogenic factor; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE INHIBITOR; MULTIPLE-MYELOMA; APOPTOSIS; CELLS; CANCER; METASTASIS; THERAPY; PROTEIN; GROWTH; BISPHOSPHONATE;

D O I：

10.1016/j.cyto.2011.01.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-beta (TGF-beta) mRNA in the mouse osteosarcoma cell line LM8. We found that statins significantly inhibited mRNA expressions of bFGF, HGF, and TGF-beta, and bFGF. HGF, and TGF-beta 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-beta mRNA expression, and bFGF, HGF, TGF-beta 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 phosphorylatecl Ala. 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-beta expression in LM8 cells. These results suggest that statins are potentially useful as anti-angiogenic agents for the treatment of osteosarcoma. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：100 / 107

页数：8

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