Novel roles of GCN2 with relevance to cancer and other major diseases

Cancer cells live in a hostile microenvironment where they are exposed to several different types of stress, such as poor nutrient and oxygen supply. All cells have developed stress-response pathways to help them survive cellular stress. The standing view is that, since cancer cells are in a hostile environment, they are more dependent on such stress-response pathways than normal cells are. GCN2 is known as a major player in several stress-response pathways, and therefore it is considered a potential target for therapy. Consistently, we have found that high GCN2 levels in cancer patients correlate with poor prognosis. Recently we have discovered novel functions of GCN2, implying that it is involved in processes other than stress responses. These include cell division, also highly relevant for carcinogenesis. Furthermore, research on other diseases has revealed that GCN2 is involved in immune responses, although its exact role is not yet characterized. However, this role might also be relevant for cancer, because cancer cells can evolve a number of mechanisms to escape the immune system. Indeed, it is an important strategy in cancer treatment to activate the immune system so that it recognizes and kills cancer cells. Our hypothesis is that, in addition to stress responses, GCN2 has important functions relevant for carcinogenesis. We suggest that GCN2 is a promising target for therapy, since a strategy targeting GCN2 will attack cancer cells on several fronts. Furthermore, GCN2 is also implicated in other diseases such as Alzheimer?s, autoimmune diseases and a fatal lung disease PVOD. We are studying the novel functions with the final goal of exploiting this knowledge in novel approaches in the treatment of these diseases.

GCN2 plays important roles in several major diseases including cancer, autoimmune diseases, Alzheimer’s disease and pulmonary veno-occlusive disease (PVOD) and is seen as a potential target for therapy. In the current project we wish to investigate novel functions of GCN2 and our findings will have impact on all the above fields. We are focusing on the cancer relevance of the novel functions. The only known function of GCN2 has been regulation of translation in stress responses. We have recently made the intriguing finding that GCN2 is required for cell division. Recent studies have shown that DNA damage arising from cell division defects can trigger immune responses. Interestingly, in the immunology field, GCN2 was long known to be important and in several autoimmune-disease models GCN2 was shown to have an immunosuppressive effect. These observations suggest that GCN2 might be important for cancer cells because of its cell-cycle and immunosuppressive functions. We will explore the novel functions of GCN2 in cell division and in immune responses. We reason that targeting GCN2 in cancer therapy would be a unique and powerful approach, since GCN2 is involved in several aspects of cancer development and progression, including stress responses, immune escape and the cell cycle, all three processes crucial for cancer progression. The idea of targeting any one of these processes is broadly exploited in existing therapies, but targeting them simultaneously is a novel approach. Furthermore, we suggest that targeting GCN2 would confer a high degree of selectivity against cancer cells since (i) it is in high demand in stress situations that cancer cells are exposed to and (ii) Cell division in normal cells is not sensitive to GCN2 depletion. Our project aims for a better understanding of the mechanistic basis of an important player in cancer and several other major diseases, which in the longer term will lead to improved therapy.