Constitutive activation of the 41-and 43-kDa mitogen-activated protein (MAP) kinases in the progression of prostate cancer to an androgen-independent state
Constitutive activation of the 41-and 43-kDa mitogen-activated protein (MAP) kinases in the progression of prostate cancer to an androgen-independent state
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DOI：
10.1111/j.1442-2042.2005.01164.x
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发表时间：
2005-10-01
影响因子：
2.6
通讯作者：
Ogawa, O
中科院分区：
文献类型：
--
作者：
Oka, H;Chatani, Y;Ogawa, O
目的：41- kda和43-kDa丝裂原活化蛋白激酶（MAPK； ERK2和ERK1）在丝裂原信号转导通路中起关键作用。我们之前证明了MAPK级联的组成激活与人类肿瘤的癌变有关。在这项研究中，我们研究了MAPK的组成激活是否与前列腺癌的雄激素依赖性进展有关。方法：在四种人类（雄激素依赖性和非依赖性）前列腺癌细胞系和大鼠前列腺癌细胞系Dunning（雄激素敏感G系和雄激素非依赖性AT-3、AT-6亚系）中，通过磷酸化形式和体外激酶测定来检测MAPK的激活。此外，将雄激素依赖性小鼠盐义癌115 （Shionogi Carcinoma 115, SC115）细胞在无雄激素的情况下连续培养，获得雄激素非依赖性细胞，检测MAPK激活的时间和程度。结果：三种人类雄激素非依赖性细胞系之一（DU145）显示MAPK的组成性激活，而雄激素依赖性细胞系（LNCaP）没有显示MAPK的激活。虽然MAPK在雄激素敏感的Dunning G细胞系中没有被激活，但MAPK在来自G细胞系的雄激素非依赖性亚系（AT-3和AT-6）中被激活。此外，当SC115细胞在无雄激素的情况下连续培养时，去除雄激素后16-24周的细胞显示MAPK激活。此外，在亚克隆细胞中，即使在没有睾酮的培养基中维持9周的细胞中也观察到MAPK的激活。结论：目前的研究结果表明，MAPK的组成性激活可能与前列腺癌中激素独立性的获得有关，并且在个体细胞中，通过MAPK信号转导途径去除雄激素后的克隆选择和激素非依赖性生长可能在相对较早的时期开始。
Aim: The 41- and 43-kDa mitogen-activated protein kinases (MAPK; ERK2 and ERK1, respectively) play pivotal roles in the mitogenic signal transduction pathway. We previously demonstrated that constitutive activation of the MAPK cascade was related to the carcinogenesis of human tumors. In this study, we examined whether constitutive activation of MAPK was related to the progression to androgen independence of prostate cancer.Methods: MAPK activation was examined by the appearance of phosphorylated forms and an in vitro kinase assay in four human (androgen-dependent and independent) prostate cancer cell lines and rat prostate cancer cell line Dunning (androgen-sensitive G line, and androgen-independent AT-3, AT-6 sublines). In addition, when androgen-dependent mouse Shionogi Carcinoma 115 (SC115) cells were serially cultured without androgen to obtain androgen-independent cells, the time and degree of MAPK activation were examined.Results: One of three human androgen-independent cell lines (DU145) showed constitutive activation of MAPK, while an androgen-dependent cell line (LNCaP) did not show MAPK activation. While MAPK were not activated in an androgen-sensitive Dunning G cell line, MAPK were activated in androgen-independent sublines (AT-3 and AT-6) derived from a G cell line. In addition, when SC115 cells were serially cultured without androgen, the cells 16-24 weeks after androgen removal showed MAPK activation. Furthermore, in subcloned cells, MAPK activation was observed even in the cells maintained for 9 weeks in medium without testosterone.Conclusions: The present ndings suggest that constitutive activation of MAPK may be associated with the acquisition of hormone independence in prostate cancer and that clonal selection after androgen removal and hormone-independent growth through the MAPK signal transduction pathway could begin at a relatively early period in the individual cells.