Induction of programmed death of tumor cells by activation of betal integrin.

研究TNIII通过刺激β1整合素活化诱导肿瘤细胞程序性死亡的分子机制。tniii诱导的β 1整合素激活诱导FAK （Tyr397）、FAK （Tyr 925）、Src （Tyr397）和Akt的去磷酸化，导致WI38VA13纤维肉瘤样细胞发生caspase非依赖性凋亡死亡。这种细胞凋亡伴随着AIF的核易位，已知与caspase非依赖性细胞凋亡有关。此外，TNIII刺激Rac活化和随后产生活性氧香料（ROS），提示ROS参与了TNIII诱导的凋亡细胞死亡。有趣的是，tniii诱导的正常成纤维细胞的反应与肿瘤细胞的反应明显不同。TNIII完全拯救了正常成纤维细胞NIH3T3免于血清剥夺的凋亡，其中Ras处于静息状态被激活。与之形成鲜明对比的是，TNIII诱导了纤维肉瘤样WI38VA13细胞的凋亡死亡，其中处于组成性活性状态的Ras短暂失活。为了解释细胞对TNIII反应的差异，构建了稳定表达Ras组成型活性突变体（NIH-V7）的NIH3T3细胞。当NIH-V7细胞与TNIII孵育时，细胞发生程序性死亡，并伴有Ras的短暂失活。因此，TNIII似乎具有通过刺激Ras激活来控制细胞存活/凋亡的能力，其中Ras的激活状态可能是细胞存活或凋亡的重要决定因素。

Molecular mechanism by which TNIII induces programmed death of tumor cells through stimulating β1 integrin activation was investigated. TNIII-induced activation of βl integrins induced dephosphorylation of FAK (Tyr397), FAK (Tyr 925), Src (Tyr 397) and Akt, resulting in caspase-independent apoptotic death of WI38VA13 fibrosarcoma-like cells. This apoptosis was accompanied by the nuclear translocation of AIF that is known to be implicated in caspase-independent apoptosis. Additionally, TNIII stimulated Rac activation and subsequent generation of reactive oxygen spices (ROS), suggesting the involvement of ROS in the TNIII-induced apoptotic cell death.Interestingly, TNIII-induced response of normal fibroblasts was clearly distinct from that of tumor cells. TNIII completely rescued mormal fibroblasts NIH3T3 from the serum-deprived apoptosis, in which Ras in a resting state was activated. In sharp contrast, TNIII elicited apoptotic death against fibrosarcoma-like WI38VA13 cells, in which Ras in a constitutively active state was transiently inactivated. To explain this difference in cellular response to TNIII, NIH3T3 cells stably expressing constitutively active mutant of Ras (NIH-V7) were constructed. When NIH-V7 cells were incubated with TNIII, the cells underwent programmed death in concomitant with a transient inactivation of Ras.Thus, TNIII appears to have the ability to control cell survival/apoptosis by stimulating Ras activation, in which the activation status of Ras may be an important determinant whether cells survive or undergo apoptosis.