PDF(Pubmed)
Abstract：
Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.
摘要：
越来越多的证据表明，caspase-3在细胞凋亡之外发挥着关键作用，在恶性转化和肿瘤发生中发挥促生存功能。然而,caspase-3在致癌转化中的非凋亡作用机制尚不清楚。在本研究中,我们表明，caspase-3在致癌混合物的外源表达诱导的恶性转化中始终被激活（c-Myc，p53DD,Oct-4和H-Ras）在体外以及在小鼠乳腺肿瘤病毒-多瘤病毒中T抗原（MMTV-PyMT）小鼠模型中。在MMTV-PyMT转基因小鼠中，caspase-3的遗传消融显着减弱了癌基因诱导的哺乳动物细胞转化并延迟了乳腺癌的进展。机械上,活性caspase-3触发核酸内切酶G（EndoG）从线粒体易位，迁移到细胞核，从而诱导Src-STAT3信号通路的磷酸化以促进致癌转化。一起来看,我们的数据表明caspase-3在促进而非抑制癌基因诱导的哺乳动物细胞恶性转化中起关键作用.
