Epidermal growth factor protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways
Epidermal growth factor protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways
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DOI：
10.1074/jbc.m511485200
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发表时间：
2006-09-15
影响因子：
4.8
通讯作者：
Kulik, George
中科院分区：
文献类型：
--
作者：
Sastry, Konduru S. R.;Karpova, Yelena;Kulik, George
已在几种细胞类型（包括成纤维细胞和上皮前列腺癌细胞）中报告了通过受体酪氨酸激酶（对磷脂酰肌醇3 '-激酶/Akt和Ras/MEK途径的抑制具有抗性）保护细胞凋亡;然而，这种作用的机制尚不清楚。在这里，我们报告说，在前列腺癌细胞中，表皮生长因子激活两个抗凋亡信号通路，对促凋亡蛋白BAD的冲击。一个信号级联通过Ras/MEK模块起作用并诱导Ser（112）上的BAD磷酸化。另一种途径主要依赖于Rac/PAK 1信号传导，其导致Ser上的BAD磷酸化（136）。这两种途径中的每一种都足以保护细胞免于凋亡，因此必须同时抑制这两种途径以阻断表皮生长因子依赖性存活。当设计针对抗凋亡机制的治疗时，应考虑抗凋亡信号通路的减少。
Protection from apoptosis by receptor tyrosine kinases, resistant to the inhibition of phosphatidylinositol 3'-kinase/Akt and Ras/MEK pathways, has been reported in several cell types, including fibroblasts and epithelial prostate cancer cells; however, mechanisms of this effect were not clear. Here we report that in prostate cancer cells, epidermal growth factor activates two antiapoptotic signaling pathways that impinge on the proapoptotic protein BAD. One signaling cascade operates via the Ras/MEK module and induces BAD phosphorylation on Ser(112). Another pathway predominantly relies on Rac/ PAK1 signaling that leads to BAD phosphorylation on Ser(136). Each of these two pathways is sufficient to protect cells from apoptosis, and therefore both have to be inhibited simultaneously to block epidermal growth factor-dependent survival. Redundancy of antiapoptotic signaling pathways should be considered when therapies targeting antiapoptotic mechanisms are designed.