p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior.
p66(Shc) restrains Ras hyperactivation and suppresses metastatic behavior.
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DOI：
10.1038/onc.2010.326
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发表时间：
2010-10-14
期刊：
影响因子：
8
通讯作者：
Terada, L. S.
中科院分区：
文献类型：
--
作者：
Ma, Z.;Liu, Z.;Wu, R-F;Terada, L. S.
正常组织细胞只有在固定在固体基质上时才能存活和增殖。相反，转化细胞在脱离后存活并增殖，通过不清楚的机制失去了附着环境。p66 Shc是一种粘着斑相关蛋白，通过RhoA依赖性机械感觉试验报告细胞附着。我们发现，人小细胞肺癌（SCLC）细胞和小鼠刘易斯肺癌（LLC），显示积极的转移行为，缺乏p66 Shc和视网膜母细胞瘤（pRB）和旁路失巢凋亡。p66 Shc在这些细胞中的重新表达恢复失巢凋亡，并提供了显著的保护，防止LLC细胞在体内的转移。值得注意的是，正常上皮细胞中p66Shc的敲低导致不受限制的Ras活化，通过RhoA的下游抑制防止失巢凋亡，但以pRB依赖性方式阻断增殖，从而模拟致癌Ras。相反，LLC和SCLC细胞显示绕过失巢凋亡所必需的组成性Ras活化，其通过p66Shc的再表达而逆转。因此，p66 Shc协调Ras依赖性的增殖和锚定感觉控制，这在高转移性肿瘤的演变中可以通过p66 Shc和pRB两者的联合丧失而被击败。
Normal tissue cells survive and proliferate only while anchored to solid substrate. Conversely, transformed cells both survive and proliferate following detachment, having lost attachment context through unclear mechanisms. p66Shc is a focal adhesion-associated protein that reports cell attachment through a RhoA-dependent mechanosensory test. We find that human small cell lung cancer (SCLC) cells and mouse Lewis lung carcinoma (LLC), which display aggressive metastatic behavior, lack both p66Shc and retinoblastoma (pRB) and bypass anoikis. Re-expression of p66Shc in these cells restores anoikis and provides striking protection from metastasis by LLC cells in vivo. Notably, knockdown of p66Shc in normal epithelial cells leads to unrestrained Ras activation, preventing anoikis through downstream suppression of RhoA but blocking proliferation in a pRB-dependent manner, thus mimicking oncogenic Ras. Conversely, LLC and SCLC cells display constitutive Ras activation necessary to bypass anoikis, which is reversed by re-expression of p66Shc. p66Shc therefore coordinates Ras-dependent control of proliferation and anchorage sensation, which can be defeated in the evolution of highly metastatic tumors by combined loss of both p66Shc and pRB.
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