Nieminen Anni I, Partanen Johanna I, Hau Annika, Klefstrom Juha
Cancer Cell Circuitry Laboratory, Institute of Biomedicine/Biochemistry and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
EMBO J. 2007 Feb 21;26(4):1055-67. doi: 10.1038/sj.emboj.7601551. Epub 2007 Feb 1.
Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL-induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.
致癌性c-Myc使细胞对TRAIL诱导的凋亡敏感，现有数据表明c-Myc通过促进线粒体凋亡途径的激活使细胞对凋亡敏感。然而，将c-Myc的线粒体效应与c-Myc依赖性的对TRAIL的敏感性联系起来的分子机制仍未得到解决。在此，我们表明TRAIL在未转化的人成纤维细胞或乳腺上皮细胞中诱导procaspase-8的微弱激活，但未能激活线粒体促凋亡效应器Bax和Bak、细胞色素c释放或下游效应器caspase-3。我们的数据与以下模型一致：致癌性c-Myc的激活通过涉及Bak激活的机制使线粒体致敏，并且这种致敏使微弱的TRAIL诱导的caspase-8信号能够激活Bax。这导致细胞色素c释放、下游半胱天冬酶的激活以及线粒体后死亡诱导信号复合物非依赖性的caspase-8-Bid活性增强。总之，c-Myc依赖性的线粒体途径致敏对于TRAIL诱导的caspase-8信号激活效应半胱天冬酶的能力以及在人类细胞中建立致死性半胱天冬酶反馈放大环至关重要。
