Jin Shengkan, White Eileen
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Autophagy. 2008 Jul;4(5):563-6. Epub 2008 Mar 3.
Autophagy plays a critical protective role maintaining energy homeostasis and protein and organelle quality control. These functions are particularly important in times of metabolic stress and in cells with high energy demand such as cancer cells. In emerging cancer cells, autophagy defect may cause failure of energy homeostasis and protein and organelle quality control, leading to the accumulation of cellular damage in metabolic stress. Some manifestations of this damage, such as activation of the DNA damage response and generation of genome instability may promote tumor initiation and drive cell-autonomous tumor progression. In addition, in solid tumors, autophagy localizes to regions that are metabolically stressed. Defects in autophagy impair the survival of tumor cells in these areas, which is associated with increased cell death and inflammation. The cytokine response from inflammation may promote tumor growth and accelerate cell non-autonomous tumor progression. The overreaching theme is that autophagy protects cells from damage accumulation under conditions of metabolic stress allowing efficient tolerance and recovery from stress, and that this is a critical and novel tumor suppression mechanism. The challenge now is to define the precise aspects of autophagy, including energy homeostasis and protein and organelle turnover, that are required for the proper management of metabolic stress that suppress tumorigenesis. Furthermore, we need to be able to identify human tumors with deficient autophagy, and to develop rational cancer therapies that take advantage of the altered metabolic state and stress responses inherent to this autophagy defect.
自噬在维持能量稳态以及蛋白质和细胞器质量控制方面发挥着关键的保护作用。这些功能在代谢应激时期以及对能量需求较高的细胞（如癌细胞）中尤为重要。在新生癌细胞中，自噬缺陷可能导致能量稳态以及蛋白质和细胞器质量控制的失败，从而在代谢应激时导致细胞损伤的积累。这种损伤的一些表现，如DNA损伤反应的激活和基因组不稳定的产生，可能促进肿瘤的起始并推动细胞自主的肿瘤进展。此外，在实体瘤中，自噬定位于代谢应激区域。自噬缺陷会损害这些区域肿瘤细胞的存活，这与细胞死亡增加和炎症相关。炎症引起的细胞因子反应可能促进肿瘤生长并加速细胞非自主的肿瘤进展。一个总的主题是，自噬保护细胞在代谢应激条件下免受损伤积累，从而实现对应激的有效耐受和恢复，并且这是一种关键且新颖的肿瘤抑制机制。现在的挑战是确定自噬的精确方面，包括能量稳态以及蛋白质和细胞器更新，这些是正确应对抑制肿瘤发生的代谢应激所必需的。此外，我们需要能够识别自噬缺陷的人类肿瘤，并开发合理的癌症治疗方法，利用这种自噬缺陷所固有的代谢状态改变和应激反应。
