Autophagy suppresses tumor progression by limiting chromosomal instability.
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.
Mathew
Robin
R
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Kongara
Sameera
S
Beaudoin
Brian
B
Karp
Cristina M
CM
Bray
Kevin
K
Degenhardt
Kurt
K
Chen
Guanghua
G
Jin
Shengkan
S
White
Eileen
E
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D015153:Blotting, Western; D002478:Cells, Cultured; D018385:Centrosome; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D004249:DNA Damage; D018450:Disease Progression; D004847:Epithelial Cells; D005455:Fluorescent Antibody Technique; D007668:Kidney / Q000166:cytology; D019656:Loss of Heterozygosity; D008660:Metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011003:Ploidies; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008869:Microtubule-Associated Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D001224:Aspartic Acid; C013195:sparfosic acid; C030986:pyrimidine; D010746:Phosphonoacetic Acid