Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis

An organ that is inflamed has an increased risk of developing cancer. Inflammation can be elicited in various ways; and intestinal inflammation and colon cancer development are often associated with a protein complex – called mTORC1 – being overactive in the tissue. This protein complex has been studied in other contexts and is known to instruct cells to produce more proteins. However, when too much protein is made too quickly, cells cannot carry out their routine quality checks. This, in turn, can lead to unfolded proteins accumulating in the cell, which is stressful and damaging, and can cause inflammation. Increased production of proteins and other biomolecules can also allow the uncontrolled growth of cancer cells. Other recently discovered proteins – called sestrins – can counteract the cancer-promoting effects of overactive mTORC1. Sestrins achieve this via several mechanisms, but as yet almost nobody had studied the role of these proteins in intestinal inflammation and colon cancer. Ro, Xue et al. deleted the genes for two members of the sestrin family, called Sestrin2 and Sestrin3, in mice and showed that their colons were more prone to inflammation. Additional analysis showed that people with ulcerative colitis – a condition in which the colon is chronically inflamed – have elevated levels of Sestrin2, whereas very low levels of Sestrin2 could be detected in tissue samples from patients with colon cancers. These data suggested that Sestrin2 might be trying to protect cells from injury and acts as a barrier to cancer formation. Ro, Xue et al. then used biochemical techniques in human cancer cells grown in the laboratory to show that Sestrin2 inhibits mTORC1, making these cells grow less. Colon cancer cells with little or no Sestrin2 were also more resistant to chemotherapy than control cells with normal levels of Sestrin2. Lastly, a type of colon cancer that is associated with inflammation grew faster in mice that lacked the gene for Sestrin2. Taken together these findings represent evidence that Sestrin2 acts as a tumor suppressor in the colon. Future experiments might investigate how losing Sestrin2 makes these cells more resistant to chemotherapy and whether sestrins act as tumor suppressors in other tissues as well.