Activation of Rap1 promotes prostate cancer metastasis.
Activation of Rap1 promotes prostate cancer metastasis.
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DOI：
10.1158/0008-5472.can-08-4269
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Casey PJ
中科院分区：
文献类型：
--
作者：
Bailey CL;Kelly P;Casey PJ
阐明前列腺癌（CaP）生存和转移的机制对于发现新的治疗靶点至关重要。单体G蛋白Rap 1与癌症肿瘤发生有关。Rap 1信号参与细胞粘附，迁移和生存的途径，这表明Rap 1可能促进与癌细胞转移相关的几个过程。CaP细胞系的检查显示具有高转移能力的细胞表现出Rap 1活性增加和负调节因子Rap 1GAP表达减少。Rap 1可以在这些细胞中被基质衍生因子（SDF-1）进一步刺激，SDF-1是一种已知调节肿瘤细胞转移和向骨的向性的激动剂。Rap 1的激活增加了CaP细胞的迁移和侵袭，通过RNAi介导的Rap 1GAP的敲低或异位表达抑制Rap 1A活性显著损害了CaP细胞的迁移和侵袭。其他研究表明整合素α4、β3和αvβ3参与Rap 1介导的CaP迁移和侵袭机制。扩展Rap 1活性在体内CaP转移中的影响，将活化的Rap 1引入CaP细胞中显著提高了异种移植小鼠模型中CaP转移的速率和发生率。这些研究提供了令人信服的证据，支持异常Rap 1激活在CaP进展中的作用，并表明靶向Rap 1信号传导可以提供一种控制这种癌症转移进展的方法。
Elucidating the mechanisms of prostate cancer (CaP) survival and metastasis are critical to the discovery of novel therapeutic targets. The monomeric G protein, Rap1, has been implicated in cancer tumorigenesis. Rap1 signals to pathways involved in cell adhesion, migration, and survival, suggesting Rap1 may promote several processes associated with cancer cell metastasis. Examination of CaP cell lines revealed cells with a high metastatic ability exhibited increased Rap1 activity and reduced expression of the negative regulator, Rap1GAP. Rap1 can be further stimulated in these cells by stromal derived factor (SDF-1), an agonist known to regulate tumor cell metastasis and tropism to bone. Activation of Rap1 increased CaP cell migration and invasion, and inhibition of Rap1A activity via RNAi-mediated knockdown or ectopic expression of Rap1GAP markedly impaired CaP cell migration and invasion. Additional studies implicate integrins α4, β3, and αvβ3 in the mechanism of Rap1-mediated CaP migration and invasion. Extending the impact of Rap1 activity in CaP metastasis in vivo, introduction of activated Rap1 into CaP cells dramatically enhanced the rate and incidence of CaP metastasis in a xenograft mouse model. These studies provide compelling evidence to support a role for aberrant Rap1 activation in CaP progression, and suggest that targeting Rap1 signaling could provide a means to control metastatic progression of this cancer.