Department of Clinical Care Medicine, Division of Pharmacology and ESR Laboratories, Kanagawa Dental College, Kanagawa, Japan.
J Pharmacol Sci. 2012;120(3):241-9. doi: 10.1254/jphs.12177fp. Epub 2012 Oct 26.
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.
我们之前报道趋化因子 CXCL14/BRAK（BRAK）在几种癌细胞中具有抗肿瘤活性，表明 BRAK 的分泌抑制了癌细胞。Ras 同源小 GTP 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剂，RhoA/ROCK 信号通路的激活刺激肿瘤侵袭和转移。我们研究了 Rho 激酶（ROCK）特异性抑制剂法舒地尔对间充质纤维肉瘤细胞（MC57）中 BRAK 分泌和肿瘤进展的影响。我们使用过表达 BRAK 的 MC57 移植的转基因小鼠证实了分泌的 BRAK 的抗肿瘤活性。此外，为了消除内源性 BRAK 的 mRNA 表达变化的影响，我们产生了表达 BRAK（MC57-BRAK）或 mock 载体（MC57-MOCK）的稳定 MC57 细胞系。法舒地尔以剂量依赖性方式显著增加 MC57-BRAK 细胞中 BRAK 的分泌。为了确定法舒地尔对肿瘤生长的影响，将 MC57-BRAK 和 MC57-MOCK 细胞移植到野生型小鼠中。法舒地尔治疗仅抑制接受 MC57-BRAK 细胞移植的小鼠的肿瘤生长。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，并表明法舒地尔治疗可能具有临床疗效。
