通过他汀类药物诱导阻断 Rho/Rho 相关卷曲螺旋蛋白激酶通路减少小鼠黑色素瘤的肺转移、细胞侵袭和黏附。
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.
机构信息
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
出版信息
J Exp Clin Cancer Res. 2010 Sep 16;29(1):127. doi: 10.1186/1756-9966-29-127.
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 α2, integrin α4, and integrin α5 and 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.
背景
黑色素瘤恶性程度高，转移潜能高；因此，需要新的治疗策略来预防细胞转移。本研究探讨了他汀类药物是否抑制 B16BL6 小鼠黑色素瘤细胞系肿瘤细胞的迁移、侵袭、黏附和转移。
方法
用细胞活力测定法评估他汀类药物对 B16BL6 细胞的细胞毒性。B16BL6 细胞静脉注射入 C57BL/6 小鼠作为实验模型。采用 Boyden 室测定法评估细胞迁移和侵袭。用 I 型胶原、IV 型胶原、纤维连接蛋白和层粘连蛋白包被板进行细胞黏附分析。用 RT-PCR、活性测定试剂盒和 Western blot 分析法分别测定基质金属蛋白酶（MMPs）的 mRNA 水平、酶活性和蛋白水平；测定变异型透明质酸受体（VLAs）的 mRNA 和蛋白水平。通过 Western blot 分析确定他汀类药物对信号转导分子的影响。
结果
我们发现，他汀类药物在不影响 B16BL6 细胞活力的浓度下，显著抑制肺转移、细胞迁移、侵袭和黏附。他汀类药物还抑制基质金属蛋白酶（MMPs）的 mRNA 表达和酶活性。此外，它们抑制整合素 α2、整合素 α4 和整合素 α5 的 mRNA 和蛋白表达，并降低 Rho、磷酸化 LIM 激酶（LIMK）和肌球蛋白轻链（MLC）的膜定位。
结论
结果表明，他汀类药物抑制 Rho/Rho 相关卷曲螺旋蛋白激酶（ROCK）通路，从而抑制 B16BL6 细胞的迁移、侵袭、黏附和转移。此外，它们明显抑制临床上明显的转移。因此，这些发现表明他汀类药物具有治疗肿瘤细胞转移的潜在临床应用。
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