Fasudil Suppresses Fibrosarcoma Growth by Stimulating Secretion of the Chemokine CXCL14/BRAK
Fasudil Suppresses Fibrosarcoma Growth by Stimulating Secretion of the Chemokine CXCL14/BRAK
复制标题
DOI：
10.1254/jphs.12177fp
复制
发表时间：
2012-11-01
影响因子：
3.5
通讯作者：
Lee, Masaichi-Chang-il
中科院分区：
文献类型：
--
作者：
Miyamoto, Chihiro;Maehata, Yojiro;Lee, Masaichi-Chang-il
我们先前报道趋化因子CXCL 14/BRAK（BRAK）在几种癌细胞中具有抗肿瘤活性，表明BRAK分泌抑制癌细胞。Ras同源小G蛋白激酶（RhoA）和Rho相关卷曲螺旋蛋白激酶（ROCK）是分泌过程的重要调节因子，RhoA/ROCK信号通路的激活刺激肿瘤侵袭和转移。我们研究了一种特异性ROCK抑制剂法舒地尔对间充质纤维肉瘤细胞（MC 57）中BRAK分泌和肿瘤进展的影响。我们证明了分泌的BRAK的抗肿瘤活性，使用MC 57移植的BRAK在过表达的转基因小鼠。此外，为了消除内源性BRAK的mRNA表达变化的影响，我们制备了表达BRAK（MC 57-BRAK）或模拟载体（MC 57-MOCK）的稳定MC 57细胞系。法舒地尔以剂量依赖性方式显著增加MC 57-BRAK细胞的BRAK分泌。为了确定法舒地尔对肿瘤生长的影响，将MC 57-BRAKE和MC 57-MOCK细胞移植到野生型小鼠中。法舒地尔治疗仅在接受MC 57-BRAKE细胞移植的小鼠中抑制肿瘤生长。这些结果表明法舒地尔通过刺激BRAK分泌抑制纤维肉瘤生长，并提示法舒地尔治疗可能具有临床疗效。[补充数字：仅可在http：//dx.doi.org/10.1254/jphs.12177FP查阅]
We previously reported that chemokine CXCL14/BRAK (BRAK) has antitumor activity in several carcinoma cells indicating that BRAK secretion suppresses carcinoma cells. Ras-homologous small GTPase (RhoA) and Rho-associated coiled-coil-containing protein kinase (ROCK) are important regulators of secretory processes, and activation of the RhoA/ROCK signaling pathway stimulates tumor invasion and metastasis. We investigated the effects of fasudil, a specific ROCK inhibitor, on BRAK secretion and tumor progression in mesenchymal fibrosarcoma cells (MC57). We demonstrated the antitumor activity of secreted BRAK using MC57 transplantation of BRAK in overexpressed transgenic mice. Further, to eliminate the influence of change in the mRNA expression of endogenous BRAK, we produced stable MC57 cell lines expressing BRAK (MC57-BRAK) or mock vector (MC57-MOCK). Fasudil significantly increased BRAK secretion by MC57-BRAK cells in a dose-dependent manner. To determine the effect of fasudil on tumor growth, MC57-BRAK and MC57-MOCK cells were transplanted into wild-type mice. Fasudil treatment suppressed tumor growth only in mice that had received MC57-BRAK cell transplants. These results indicate that fasudil inhibits fibrosarcoma growth by stimulating BRAK secretion and suggests that fasudil therapy might have clinical efficacy. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.12177FP]