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

Nature Medicine volume 21, pages 906–913 (2015)Cite this article

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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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References

  1. Weir, H.K. et al. Annual report to the nation on the status of cancer, 1975–2000, featuring the uses of surveillance data for cancer prevention and control. J. Natl. Cancer Inst. 95, 1276–1299 (2003).

    Article  PubMed  Google Scholar 

  2. Karin, M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb. Perspect. Biol. 1, a000141 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hugot, J.P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Dupaul-Chicoine, J. et al. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32, 367–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Zaki, M.H. et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Allen, I.C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J. Exp. Med. 207, 1045–1056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zaki, M.H., Vogel, P., Body-Malapel, M., Lamkanfi, M. & Kanneganti, T.D. IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J. Immunol. 185, 4912–4920 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625–1636 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen, G.Y., Liu, M., Wang, F., Bertin, J. & Nunez, G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol. 186, 7187–7194 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hu, B. et al. Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc. Natl. Acad. Sci. USA 110, 9862–9867 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl. Acad. Sci. USA 108, 9601–9606 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl. Acad. Sci. USA 107, 21635–21640 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fernandes-Alnemri, T., Yu, J.W., Datta, P., Wu, J. & Alnemri, E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. DeYoung, K.L. et al. Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15, 453–457 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Woerner, S.M. et al. Microsatellite instability of selective target genes in HNPCC-associated colon adenomas. Oncogene 24, 2525–2535 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Woerner, S.M. et al. The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosom. Cancer 46, 1080–1089 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Dihlmann, S. et al. Lack of Absent in Melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival in colorectal cancer patients. Int. J. Cancer 135, 2387–2396 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Choubey, D., Walter, S., Geng, Y. & Xin, H. Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2 (absent in melanoma) gene from the 200-gene family. FEBS Lett. 474, 38–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Chen, I.F. et al. AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model. Mol. Cancer Ther. 5, 1–7 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Patsos, G., Germann, A., Gebert, J. & Dihlmann, S. Restoration of absent in melanoma 2 (AIM2) induces G2/M cell cycle arrest and promotes invasion of colorectal cancer cells. Int. J. Cancer 126, 1838–1849 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Neufert, C., Becker, C. & Neurath, M.F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat. Protoc. 2, 1998–2004 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Powrie, F., Leach, M.W., Mauze, S., Caddle, L.B. & Coffman, R.L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Dinarello, C.A. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev. 29, 317–329 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moser, A.R., Pitot, H.C. & Dove, W.F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Rakoff-Nahoum, S. & Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317, 124–127 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Lee, J., Li, L., Gretz, N., Gebert, J. & Dihlmann, S. Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers. Oncogene 31, 1242–1253 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Dhillon, A.S., Hagan, S., Rath, O. & Kolch, W. MAP kinase signalling pathways in cancer. Oncogene 26, 3279–3290 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Grivennikov, S.I. & Karin, M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev. 21, 11–19 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Parsons, D.W. et al. Colorectal cancer: mutations in a signalling pathway. Nature 436, 792 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Stephens, L. et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710–714 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Sarbassov, D.D., Guertin, D.A., Ali, S.M. & Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Feng, J., Park, J., Cron, P., Hess, D. & Hemmings, B.A. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J. Biol. Chem. 279, 41189–41196 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Li, Y. et al. Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation. J. Biol. Chem. 288, 13215–13224 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu, D., Huang, J. & Basu, A. Protein kinase Cε activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-α-induced cell death. J. Biol. Chem. 281, 22799–22807 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Li, Z. et al. Effect of adenovirus-mediated PTEN gene on ulcerative colitis-associated colorectal cancer. Int. J. Colorectal Dis. 28, 1107–1115 (2013).

    Article  PubMed  Google Scholar 

  40. Ma, J. et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J. Natl. Cancer Inst. 91, 620–625 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, Y. et al. Capture and 3D culture of colonic crypts and colonoids in a microarray platform. Lab Chip 13, 4625–4634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Miyoshi, H. & Stappenbeck, T.S. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat. Protoc. 8, 2471–2482 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang, L. et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 64, 4394–4399 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Roberts, S.A. et al. Ku is a 5′-dRP/AP lyase that excises nucleotide damage near broken ends. Nature 464, 1214–1217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hosoi, Y. et al. Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int. J. Oncol. 25, 461–468 (2004).

    CAS  PubMed  Google Scholar 

  47. An, J. et al. DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein. Mol. Cancer 7, 32 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Cooper, A. et al. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 498, 376–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Mariathasan, S. et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430, 213–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Ostanin, D.V. et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G135–G146 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Petrucelli, A., Umashankar, M., Zagallo, P., Rak, M. & Goodrum, F. Interactions between proteins encoded within the human cytomegalovirus UL133-UL138 locus. J. Virol. 86, 8653–8662 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.).

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  1. Justin E Wilson and Alex S Petrucelli: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA

    Justin E Wilson, Alex S Petrucelli, Liang Chen, A Alicia Koblansky, Agnieszka D Truax, Yoshitaka Oyama, W June Brickey, Wei-Chun Chou, Dale A Ramsden & Jenny P Y Ting

  2. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA

    Justin E Wilson, Alex S Petrucelli, Liang Chen, A Alicia Koblansky, Agnieszka D Truax, Yoshitaka Oyama, W June Brickey, Wei-Chun Chou & Jenny P Y Ting

  3. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA

    Justin E Wilson, Alex S Petrucelli, Liang Chen, A Alicia Koblansky, Agnieszka D Truax, Yoshitaka Oyama, W June Brickey, Wei-Chun Chou & Jenny P Y Ting

  4. Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA

    Arlin B Rogers

  5. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Yuli Wang & Nancy L Allbritton

  6. The American Association of Immunologists, Bethesda, Maryland, USA

    Monika Schneider

  7. Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, Florida, USA

    Marcus Mühlbauer & Christian Jobin

  8. Department of Infectious Diseases & Pathology, University of Florida College of Medicine, Gainesville, Florida, USA

    Marcus Mühlbauer & Christian Jobin

  9. Department of Biology, Drew University, Madison, New Jersey, USA

    Brianne R Barker

  10. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA

    Dale A Ramsden

  11. Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA

    Dale A Ramsden

  12. Department of Biology, Franklin & Marshall College, Lancaster, Pennsylvania, USA

    Beckley K Davis

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Contributions

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.

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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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