Autophagy, a process responsible for bulk protein and organelle degradation is implicated in tumor suppression. In humans, monoallelic deletion of beclin 1 is prevalent in tumors, and mice with targeted allelic deletion of beclin 1 have increased cancer rates. However, exactly how autophagy suppresses cancer development is not clear. On the other hand, a fundamental and conserved function of autophagy is alleviating metabolic stress. Autophagy is found to be activated at the center of a tumor to mitigate the metabolic stress caused by inefficient oxygen and nutrient diffusion, and support cell survival. It is also not clear how the loss of a survival mechanism paradoxically increases tumorigenicity. Here we show that autophagy deficiency promotes chromosome instability by increasing abnormal centrosome duplication and mitosis under metabolic stress. Time-lapse microscopy showed that under amino acid deprivation the T-antigen immortalized mouse embryonic fibroblasts (iMEFs) derived from mice with a targeted deletion of an essential autophagy gene, atg5, exhibited an increased frequency of aberrant mitosis that included tripolar division and endomitosis as compared to their wild type counterparts. Metabolic stress significantly increased the percentage of the atg5-/- cells containing 3 or more centrosomes, while it had little effect on the atg5+/+ cells. Similarly, knocking down the expression of another essential autophagy gene beclin 1 with siRNA in the atg5+/+ iMEFs led to a similar phenotype as observed in the atg5-/- cells. Furthermore, the atg5-/- cells exhibited higher chromosome instability than the atg5+/+ cells under metabolic stress as determined by the rate of gene amplification. Together, our results suggest that autophagy may suppress tumor development through reducing chromosome instability by mitigating metabolic stress, thereby preventing tumor progression.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA