The role of IMPACT/GCN1/GCN2 translational control module in Adenocarcinoma of Pancreas

Abstract

Pancreatic Adenocarcinoma is one of the most deadly Cancers in the world although the incidence is not as high as other types of solid tumors. In Brazil, it accounts for 2% of all Cancers and 4% of deaths from this disease. The main cause of so many deaths is the difficulty of an early and accurate diagnosis, causing the Cancer to be discovered already in advanced stages. As therapy, in addition to the surgical procedure, chemotherapy and radiotherapy may be used associated or not. However, even with the available treatment options, a good portion of the patients is resistant to the treatments. Most of the studies related to this disease are focused mainly on the genetic alterations found in the tumor. The translation process is a very important cellular function that allows the cell to respond quickly to environmental stimuli. Phosphorylation of the ± subunit of IF2 is one of the main focuses of translation control, its phosphorylation is done by several kinases that respond to environmental stimuli. GCN2 responds to the lack of amino acids, phosphorylating eIF2± and inhibiting the general translation. GCN2 is regulated by GCN1 activity, being activated when binding to GCN1. The IMPACT protein also participates in the regulation of GCN2 by the interaction with GCN1. When IMPACT binds to GCN1, it prevents binding of this protein to GCN2, and GCN2 in turn, loses the phosphorylating activity of eIF2±, stimulating translation. In the cBioPortal portal, alterations were found in genes that encode these 3 proteins in Pancreatic Adenocarcinoma. In the UT Southwester Medical Center database, 23% of the cases present alterations in one or more of these genes and the main alterations were found in the IMPACT gene (8.3% deletions and 6.8% amplifications). Diagnosis and treatment, it is of great relevance to unravel the molecular mechanisms and to search for possible therapeutic approaches. Thus, this project seeks to understand the role of the IMPACT-GCN1- GCN2 translational control module in Pancreatic Adenocarcinoma. (AU)