Known for its antipathogenic role, the inflammasome protein AIM2 also helps prevent tumors. One new study suggests that the protein's tumor suppressor activity stems from its ability to inhibit AKT. A second study indicates that the protein curtails proliferation of intestinal stem cells and controls the composition of the intestinal microbiota.
Two recent papers explain how the inflammasome protein AIM2 protects against colon cancer, suggesting strategies to prevent and treat the disease.
AIM2 detects double-stranded DNA from bacteria and viruses and forms part of the inflammasome, an infection-fighting protein complex. Previous research also suggests that AIM2 is a tumor suppressor because its expression is turned down or off in many melanomas, colorectal cancers, and prostate tumors. However, researchers don't know precisely how AIM2 affects tumorigenesis, so two independent teams investigated its role.
In one study, Justin Wilson, PhD, of the University of North Carolina in Chapel Hill, and colleagues dosed mice with two compounds that induce colon tumors. Mice lacking AIM2 developed more precancerous intestinal polyps and colon tumors than did controls. The researchers also studied mice that carry a mutation in the gene adenomatous polyposis coli. In humans, this gene is mutated in many sporadic colon cancers and a hereditary form of the disease. Mice with the mutation spontaneously developed colorectal and intestinal tumors, and the team determined that losing AIM2 increased their tumor load.
The researchers found that colon tissue from the AIM2-lacking mice showed increased levels of activated AKT. A promoter of cell survival and proliferation, AKT is often overactive in tumors. As Wilson and colleagues reported last month in Nature Medicine, AIM2 teams up with another protein, DNA-PK, to block AKT.
In the other study, Thirumala-Devi Kanneganti, PhD, of St. Jude Children's Research Hospital in Memphis, TN, and colleagues discovered that AIM2 also curbs tumor growth by curtailing proliferation of stem cells from the colon epithelium. In culture, these cells divided more rapidly if they were missing AIM2. The team also saw increased intestinal stem cell proliferation and faster tumor growth in mice that lacked AIM2.
The protein might also influence tumor growth by controlling the composition of the intestinal microbiota. AIM2′s absence altered the abundance of several bacterial species—including two species linked to colon tumors—the researchers reported last month in Cell.
Both studies agree that AIM2′s ability to suppress tumor growth is independent of its function as an inflammasome protein. Both suggest that AIM2 inhibits AKT, and both point to avenues for therapy or prevention.
Wilson and colleagues gave the same tumor-inducing compounds they'd used before to AIM2-lacking mice. One group of animals also received an AKT blocker, and those mice developed fewer polyps and tumors than did mice that received a placebo.
“If you can inhibit AKT, you might be able to treat tumors” in which AIM2 is scarce or absent, says Jenny P. Y. Ting, PhD, senior author of the Nature Medicine paper. No AKT inhibitors are approved for treating cancer, but several are under development or in clinical trials.
Kanneganti's team evaluated whether changes in the animals' intestinal microbiota reduced tumor formation. They housed AIM2-lacking mice with normal animals. The rodents gradually acquired the bacteria of their cage-mates, which reduced tumor formation in the AIM2-deficient mice. “Mice lacking AIM2 have a distinct microbial ecology,” says lead author Si Ming Man, PhD, raising the possibility that modifying gut microbiota might prevent colon cancer in patients.
Experts praised the work of both teams. “The two papers are very significant and will give us a basis to explore the role of the human AIM2 protein in development of epithelial cancers,” says Divaker Choubey, PhD, of Ohio's University of Cincinnati College of Medicine.
That both groups demonstrated that the role of AIM2 in preventing colon cancer is important, says Naeha Subramanian, PhD, of the Institute for Systems Biology in Seattle, WA. “Two groups published at the same time, and their conclusions are concordant.”