929-细胞死亡及周期阻滞基本信号通路课件.pptVIP

● Autophagy Promotes Tumor Cell Survival and Restricts Necrosis, Inflammation, and Tumorigenesis Defective apoptosis renders immortalized epithelial cells highly tumorigenic, but how this is impacted by other common tumor mutations is not known. In apoptosis-defective cells, inhibition of autophagy by AKT activation or by allelic disruption of beclin1 confers sensitivity to metabolic stress by inhibiting an autophagy-dependent survival pathway. While autophagy acts to buffer metabolic stress, the combined impairment of apoptosis and autophagy promotes necrotic cell death in vitro and in vivo. Thus, inhibiting autophagy under conditions of nutrient limitation can restore cell death to apoptosis-refractory tumors, but this necrosis is associated with inflammation and accelerated tumor growth. Thus, autophagy may function in tumor suppression by mitigating metabolic stress and, in concert with apoptosis, by preventing death by necrosis. (Degenhardt K et al. Cancer Cell, 10: 51-64, 2006) Autophagy is a survival mechanism activated in response to metabolic stress. In normal tissues autophagy plays a major role in energy homeostasis through catabolic self-digestion of damaged proteins and organelles. Contrary to its survival function, autophagy defects are implicated in tumorigenesis suggesting that autophagy is a tumor suppression mechanism. Although the complex role of functional autophagy in tumors is not known, it likely involves mitigation of cellular damage leading to chromosomal instability. We developed model systems that permits the study of tissue- as well as gene-specific tumor promoting functions. We successfully employed this strategy to generate isogenic, immortal epithelial cell lines from wild-type and mutant mice deficient in essential autophagy genes such as beclin 1 (beclin 1+/-) and atg5 (atg 5-/-). As these cell lines are amenable to further genetic manipulation, they allowed us to generate cell lines with apoptosis defects and stable expression of