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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins
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Aspartic Acid / analogs & derivatives
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Aspartic Acid / pharmacology
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Autophagy / physiology*
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Autophagy-Related Protein 5
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Beclin-1
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Blotting, Western
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Cells, Cultured
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Centrosome
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Chromosomal Instability*
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Chromosome Aberrations
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DNA Damage
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Disease Progression
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Epithelial Cells
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Fluorescent Antibody Technique
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Kidney / cytology
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Loss of Heterozygosity
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Metabolism / physiology
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Mice
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Mice, Knockout
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / physiology*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology*
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Phosphonoacetic Acid / analogs & derivatives
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Phosphonoacetic Acid / pharmacology
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Ploidies
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrimidines / biosynthesis
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Signal Transduction
Substances
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Apoptosis Regulatory Proteins
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Atg5 protein, mouse
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Autophagy-Related Protein 5
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Beclin-1
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Becn1 protein, mouse
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Microtubule-Associated Proteins
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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Aspartic Acid
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sparfosic acid
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pyrimidine
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Phosphonoacetic Acid
Associated data
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RefSeq/AC_109608
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RefSeq/NM_023525