Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway

被引：87

作者：

Kidera Y. ^{[1
,2
]}

Tsubaki M. ^{[1
]}

Yamazoe Y. ^{[1
,2
]}

Shoji K. ^{[3
]}

Nakamura H. ^{[3
]}

Ogaki M. ^{[3
]}

Satou T. ^{[4
]}

Itoh T. ^{[4
]}

Isozaki M. ^{[1
,2
]}

Kaneko J. ^{[1
]}

Tanimori Y. ^{[1
,2
]}

Yanae M. ^{[1
,5
]}

Nishida S. ^{[1
]}

机构：

[1] Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae

[2] Department of Pharmacy, Kinki University Hospital, Osakasayama

[3] Department of Pharmacy, Higahiosaka City General Hospital, Higashi-osaka

[4] Department of Pathology, Kinki University School of Medicine, Osakasayama

[5] Department of Pharmacy, Sakai Hospital, Kinki University School of Medicine, Sakai

来源：

Journal of Experimental & Clinical Cancer Research | / 29卷 / 1期

关键词：

Simvastatin; Fluvastatin; Myosin Light Chain; Cell Survival Rate; Collagenase Activity;

D O I：

10.1186/1756-9966-29-127

中图分类号：

学科分类号：

摘要：

Background. Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. Methods. The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. Results. We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin 2, integrin 4, and integrin 5and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). Conclusions. The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis. © 2010 Kidera et al; licensee BioMed Central Ltd.

引用

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