Autophagy suppresses tumor progression by limiting chromosomal instability

  1. Robin Mathew 1 ,2,
  2. Sameera Kongara 2 ,3,
  3. Brian Beaudoin 2 ,3,
  4. Cristina M. Karp 2,
  5. Kevin Bray 2 ,3,
  6. Kurt Degenhardt 2 ,3,
  7. Guanghua Chen 2,
  8. Shengkan Jin 4 ,5, and
  9. Eileen White 1 ,2 ,3 ,5 ,6
  1. 1 University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA;
  2. 2 Center for Advanced Biotechnology and Medicine, Rutgers University Piscataway, New Jersey 08854, USA;
  3. 3 Department of Molecular Biology and Biochemistry, Rutgers University Piscataway, New Jersey 08854, USA;
  4. 4 Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA;
  5. 5 The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA

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

Footnotes

  • ↵ 6 Corresponding author.

    ↵ 6 E-MAIL ewhite{at}cabm.rutgers.edu; FAX (732) 235-5795.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1545107

    • Received February 23, 2007.
    • Accepted April 12, 2007.

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