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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / complications
  • Colonic Neoplasms / prevention & control*
  • DNA-Activated Protein Kinase / physiology*
  • DNA-Binding Proteins / physiology*
  • Female
  • HCT116 Cells
  • Humans
  • Inflammasomes / physiology*
  • Intestinal Polyps / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / physiology*


  • Aim2 protein, mouse
  • DNA-Binding Proteins
  • Inflammasomes
  • DNA-Activated Protein Kinase
  • Proto-Oncogene Proteins c-akt