Autophagy suppresses tumor progression by limiting chromosomal instability

Abstract

Autophagy is a bulk degradation process that promotes survival under metabolic stress, but it can also be a means of cell death if executed to completion. Monoallelic loss of the essential autophagy gene beclin1 causes susceptibility to metabolic stress, but also promotes tumorigenesis. This raises the paradox that the loss of a survival pathway enhances tumor growth, where the exact mechanism is not known. Here, we show that compromised autophagy promoted chromosome instability. Failure to sustain metabolism through autophagy was associated with increased DNA damage, gene amplification, and aneuploidy, and this genomic instability may promote tumorigenesis. Thus, autophagy maintains metabolism and survival during metabolic stress that serves to protect the genome, providing an explanation for how the loss of a survival pathway leads to tumor progression. Identification of this novel role of autophagy may be important for rational chemotherapy and therapeutic exploitation of autophagy inducers as potential chemopreventive agents.[Keywords: Autophagy; beclin1; genomic instability; apoptosis; cancer] Received February 23, 2007; revised version accepted April 12, 2007. Autophagy is an evolutionarily conserved catabolic process involving regulated turnover and elimination of proteins and cellular organelles, such as peroxisomes, mitochondria, and endoplasmic reticulum, through the lysosomal degradation pathway (Mizushima 2005). The process of autophagy is characterized by the formation of double-membrane cytosolic vesicles, known as autophagosomes, that are essential for the lysosomal targeting of these organelles. In yeast, a number of autophagy-related genes (referred to as atg) have been identified that regulate the formation of autophagosomes and the autophagy process (Klionsky et al. 2003). Several mammalian homologs of these yeast genes have been identified (Levine and Klionsky 2004), among which the essential autophagy genes atg5 and atg7 have been most informative in demonstrating a role for autophagy in maintaining metabolism and homeostasis in mammalian development.Autophagy, constitutively active at low levels, is robustly activated under metabolic stress. Autophagy plays an important role in development, as mice deficient in autophagy due to complete deficiency of beclin1 (atg6/vps30), another essential autophagy gene, die early in embryogenesis (Yue et al. 2003). Mice lacking atg5 fail to survive the neonatal starvation period and die perinatally, suggesting that autophagy plays an important role in the maintenance of energy homeostasis (Kuma et al. 2004). Thus, autophagy functions as an alternative cellular energy source to maintain normal metabolism during development and starvation by recycling cytoplasm and macromolecules (Jin and White 2007). Furthermore, targeted deletion of atg5 and atg7 in the central nervous system results in accumulation of polyubiquitinated proteins leading to neurodegeneration, revealing a housekeeping role for autophagy in the regulation of long-lived or damaged proteins...

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