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

Justin E. Wilson, Alex S. Petrucelli, Liang Chen, A. Alicia Koblansky, Agnieszka D. Truax, Yoshitaka Oyama, Arlin B. Rogers, W. June Brickey, Yuli Wang, Monika Schneider, Marcus Mühlbauer, Wei Chun Chou, Brianne R. Barker, Christian Jobin, Nancy L. Allbritton, Dale A. Ramsden, Beckley K. Davis, Jenny P.Y. Ting

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

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 â '/â '/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 â '/â ' mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.

Original languageEnglish (US)
Pages (from-to)906-913
Number of pages8
JournalNature Medicine
Volume21
Issue number8
DOIs
StatePublished - Aug 8 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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