Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression.
Melatonin decreases breast cancer metastasis by modulating Rho-associated kinase protein-1 expression.
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DOI：
10.1111/jpi.12270
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发表时间：
2016-01
影响因子：
10.3
通讯作者：
Zuccari DA
中科院分区：
文献类型：
--
作者：
Borin TF;Arbab AS;Gelaleti GB;Ferreira LC;Moschetta MG;Jardim-Perassi BV;Iskander AS;Varma NR;Shankar A;Coimbra VB;Fabri VA;de Oliveira JG;Zuccari DA
转移的发生依赖于细胞迁移/侵袭机制，是影响乳腺癌预后的重要因素，而细胞迁移/侵袭机制可由rho相关激酶蛋白（ROCK-1）等调控和效应分子控制。该蛋白的表达增加可促进肿瘤生长和转移，这可以通过ROCK-1抑制剂加以限制。褪黑素显示出抑瘤、抗转移和抗血管生成的作用，并可以调节ROCK-1的表达。褪黑素和特异性ROCK-1抑制剂（Y27632）联合治疗转移性和非转移性乳腺癌细胞系。体外检测细胞活力、细胞迁移/侵袭、ROCK-1基因表达和蛋白表达。雌性胸腺裸鼠分别用褪黑素或Y27832治疗2周和5周，进行体内肺转移研究。通过x线计算机断层扫描和单光子发射计算机断层扫描（SPECT）以及ROCK-1和细胞角蛋白的免疫组织化学检测评估转移灶。褪黑素和Y27632处理降低了两种细胞系的细胞活力和侵袭/迁移，降低了转移细胞中ROCK-1基因的表达和非转移细胞系中蛋白质的表达。在治疗组中，SPECT图像发现的“热点”（肺转移）数量明显减少。ROCK-1蛋白在治疗组转移灶中的表达也有所降低。褪黑素在体外和体内均显示出对转移性乳腺癌的有效控制作用，不仅可以抑制肿瘤细胞的增殖，还可以直接拮抗ROCK-1抑制导致的细胞转移机制。当使用Y27632时，效果与褪黑激素治疗相似。
The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of ‘hot’ spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment.