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Nat Med. 2015 Aug;21(8):906-13. doi: 10.1038/nm.3908. Epub 2015 Jun 24.

Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt.

Author information

1
1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA.
2
Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA.
3
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
4
The American Association of Immunologists, Bethesda, Maryland, USA.
5
1] Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, Florida, USA. [2] Department of Infectious Diseases &Pathology, University of Florida College of Medicine, Gainesville, Florida, USA.
6
Department of Biology, Drew University, Madison, New Jersey, USA.
7
1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA.
8
Department of Biology, Franklin &Marshall College, Lancaster, Pennsylvania, USA.

Abstract

The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.

PMID:
26107252
PMCID:
PMC4529369
DOI:
10.1038/nm.3908
[Indexed for MEDLINE]
Free PMC Article

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