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−/−/ApcMin/+ than in APCMin/+ 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.

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Figure 1: AIM2 is distinct from ASC during colitis-associated colon cancer.
Figure 2: AIM2 protects against colon tumorigenesis.
Figure 3: AIM2 negatively regulates Akt activity in vitro and in vivo.
Figure 4: AIM2 restricts cell proliferation and promotes apoptosis.
Figure 5: AIM2 associates with DNA-PK and restricts its activity and Akt phosphorylation.

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Acknowledgements

We thank E.H. Guthrie for technical assistance and I.C. Allen from the Department of Biomedical Sciences and Pathobiology at Virginia Tech for technical advice regarding the CAC model. P.K. Lund and S. Ding from the Department of Cell Biology and Physiology at UNC for their helpful discussions and technical advice pertaining to the ApcMin/+ model of spontaneous intestinal cancer; the Center for Gastrointestinal Biology and Disease (CGIBD) at UNC for providing core and technical support; and the Department of Microbiology and Immunology Flow Cytometry Core Facility at UNC for providing core and technical support. This work was supported by National Institute of Health (NIH) grants RO1-CA156330 (National Cancer Institute), U19-AI067798 (National Institute of Allergy and Infectious Disease (NIAID)), R37-AI029564 (NIAID) and P01 DK094779 (National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)) (J.P.-Y.T.). J.E.W. was supported in part by the NIH postdoctoral fellowship F32-K088417-01 (NIDDK) and in part by the American Cancer Society, PF-13-401-01-TBE. This work was also supported by the NIH grants R01 EY024556 (National Eye Institute) (N.L.A. and Y.W.) and R15 DK098754 (NIDDK) (B.K.D.).

Author information

J.E.W. and A.S.P. contributed equally to this manuscript. J.E.W., A.S.P. and J.P.-Y.T designed the experiments and wrote the manuscript with input from B.K.D. and D.A.R. J.E.W., A.S.P. and L.C. performed most of the analyses. A.S.P. generated the AIM2 constructs and performed lentivirus transductions. W.-C.C. assisted in generating primary fibroblasts. M.S. performed the qPCR cytokine experiments. A.A.K, A.D.T. and W.J.B. assisted in the CAC and APCmin/+ animal studies. A.B.R. performed the histopathological scoring. L.C. performed the clinical scoring. Y.W. and N.L.A. developed and generated the primary organoid cultures. B.R.B. and Y.O. performed the flow cytometric analysis. M.M. and C.J. performed and oversaw the mini-endoscopy. All contributing authors have agreed to submission of this manuscript for publication.

Correspondence to Jenny P Y Ting.

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Wilson, J., Petrucelli, A., Chen, L. et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med 21, 906–913 (2015). https://doi.org/10.1038/nm.3908

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