CONICET | Buscador de Institutos y Recursos Humanos

Colorectal cancer (CRC) is the third most common diagnosed cancer globally and the thirdmost frequent cause of cancer-related deaths in Argentina. In colorectal tumors the firstoncogenic mutation provides selective advantage to the epithelial cell that multiplies andgenerates a microadenoma. In the majority of sporadic colorectal tumors these ?initiatory?mutations frequently occur in genes associated to the Wnt pathway. Subsequent mutations inother genes, such as TP53, PTEN, SMAD4, KRAS and PIK3CA are followed by clonalexpansion of transformed cells. Despite advances in surgical techniques, improvedchemotherapy and early detection, CRC is still associated with a relatively poor prognosis. Atleast 40% of patients who undergo resection of the primary tumor die within 5 years. CRC isa major health problem demanding new approaches for its prevention and treatment.Several lines of evidence indicate that metformin, a first-line oral anti-diabetic agent for type2 diabetes, has an antitumor effect. A recent meta-analysis that included 23.255 participantsrevealed that diabetic patients with CRC taking metformin achieved an survival benefit of44% compared with non-metformin users. The mechanism mediating this effect has not beenelucidated.Results from our laboratory show that metformin inhibits the proliferation of human cellsderived from primary adenocarcinoma of the colon by a mechanism that involves ß -cateninand E-cadherin. Specifically, we found that metformin: 1- inhibits the phosphorylation of ß-catenin Ser552, 2- promotes the plasma membrane redistribution of ß-catenin and E-cadherin,3- inhibits ß-catenin-mediated transcription, and 4- inhibits cell´s motility. Overall, our studiesreveal two novel metformin targets and suggest a mechanism by which this anti-diabetic druginterferes with CRC development.