title: Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt.
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.
authors.affiliation: 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.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: 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.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Petrucelli
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: A Alicia
authors.initials: AA
authors.lastname: Koblansky
authors.affiliation: 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.
authors.forename: Agnieszka D
authors.initials: AD
authors.lastname: Truax
authors.affiliation: 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.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Oyama
authors.affiliation: Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Rogers
authors.affiliation: 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.
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The American Association of Immunologists, Bethesda, Maryland, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Schneider
authors.affiliation: 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.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mühlbauer
authors.affiliation: 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.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Department of Biology, Drew University, Madison, New Jersey, USA.
authors.forename: Brianne R
authors.initials: BR
authors.lastname: Barker
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.affiliation: Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Allbritton
authors.affiliation: 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.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Ramsden
authors.affiliation: Department of Biology, Franklin &Marshall College, Lancaster, Pennsylvania, USA.
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.affiliation: 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.
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D003092:Colitis / Q000150:complications; D003110:Colonic Neoplasms / Q000517:prevention & control*; D051747:DNA-Activated Protein Kinase / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007417:Intestinal Polyps / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt