Activation of the RaIGEF/ral pathway promotes prostate cancer metastasis to bone
Activation of the RaIGEF/ral pathway promotes prostate cancer metastasis to bone
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DOI：
10.1128/mcb.00955-07
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发表时间：
2007-11-01
影响因子：
5.3
通讯作者：
Kelly, Kathleen
中科院分区：
文献类型：
--
作者：
Yin, JuanJuan;Pollock, Claire;Kelly, Kathleen
转移的一个标志是器官特异性。然而，人们对靶器官中肿瘤细胞定植和生长的潜在信号通路知之甚少。由于酪氨酸激酶受体激活通常与前列腺癌进展相关，因此我们研究了常见的信号中介、激活的 Ras 在前列腺癌转移中的作用。检测了 Ras 下游的三个效应通路，即 Raf/细胞外信号调节激酶 (ERK)、磷脂酰肌醇 3-激酶和 Ral 鸟嘌呤核苷酸交换因子 (RaIGEF)，以确定它们促进致瘤、非转移性人前列腺癌细胞系 DU145 转移的能力。致癌Ras促进DU145向多个器官的转移，包括骨和脑。 Raf/ERK 通路的激活刺激大脑的转移定植，而 RaIGEF 通路的激活导致骨转移，这是前列腺癌转移最常见的器官部位。此外，转移性PC3细胞系中RaIA的缺失抑制了骨转移，但不影响皮下肿瘤生长。 RaI的缺失似乎抑制了前列腺癌细胞在骨中的扩张生长，而归巢和初始定植受到的影响较小。这些数据扩展了我们对 RaI 通路功能作用的理解，并开始识别与器官特异性转移相关的信号通路。
A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RaIGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RaIGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RaIA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of RaI appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the RaI pathway and begin to identify signaling pathways relevant for organ-specific metastasis.