A tumor suppressor is identified as an inhibitor of inflammatory pathways
Scientists at the National Cancer Institute (NCI) have found that a protein, FBXW7, which acts as a tumor suppressor, is also important for the reduction in strength of inflammatory pathways. It has long been recognized that a complex interaction exists between cancer causing mechanisms and inflammation. For example, inflammatory signaling molecules such as another protein known as interleukin-6 normally functions to combat infections. However, these molecules can also be produced in cancer tissue where they can promote malignant progression. The FBXW7 protein is known to help reduce the levels of many cancer-promoting proteins within cancer cells. This study is the first to describe how FBXW7 acts in cancer cells as well as in cells of the immune system to attenuate inflammatory signaling, which is accomplished by reducing the levels of C/EBPdelta, a protein that regulates the expression of many genes. The investigators showed that temporarily reducing the levels of FBXW7 in mice was sufficient to increase serum levels of interleukin-6, which is known to be associated with increased cancer risk and chronic inflammatory diseases. On the other hand, mouse and human cells with reduced levels of C/EBPdelta had more FBXW7 and blunted inflammatory signaling. These results provide an important mechanistic link between tumor suppression and inhibition of inflammation. The study, headed by Esta Sterneck, Ph.D., at NCI’s Center for Cancer Research, and colleagues, was published online in Nature Communications on April 9, 2013.
Because FBXW7 acts in cooperation with an enzyme known as GSK-3β, this study also implicates GSK-3beta as an inhibitor of the inflammatory response. Paradoxically, GSK-3beta is mostly known as a pro-inflammatory agent and drugs that inhibit its activity are being developed for diseases such as Alzheimer’s, cancer, diabetes, obesity, and immune disorders. This work provides further evidence for a dual role that might complicate clinical applications of drugs targeted at inhibiting GSK-3beta. However, these new findings may be exploited to gain insights into the molecular events governing acute versus chronic inflammation in cancer and other diseases.