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.

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...

Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.

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The proapoptotic protein Bim is expressed de novo following withdrawal of serum survival factors. Here, we show that BimÀ/À fibroblasts and epithelial cells exhibit reduced cell death following serum withdrawal in comparison with their wild-type counterparts.