A NOVEL PI3K-AKT-GLI3 AXIS ACTIVATES THE MACHINERY CONTROLLING AUTOPHAGY IN PANCREATIC CANCER CELLS

LO RE, A; ALMADA, LL; PARDO, R; MOLEJON, MI; ELSAWA, SF; VACCARO, MI; FERNANDEZ-ZAPICO, ME

Encuentro; 41st Annual Meeting of the American Pancreatic Association, November 3-6, 2010, Chicago, Illinois.; 2010

Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells. It has been suggested that autophagy can acts in tumor promotion and progression, however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we have found that the transmembrane protein VMP1, a key mediator of autophagy, is upregulated in pancreatic cancer cells undergoing starvation. Analysis of the mechanism revealed that GLI3, an effector of the Hedgehog pathway regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter. We have found that the histone acetyltransferase p300 complex with GLI3 and cooperates with this transcription factor to activate VMP1 expression. RNAi knockdown of p300 impairs starvation as well as GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT axis as the signaling mediator modulating the activity of this novel GLI3-p300 transcriptional complex. This pathway is activated in pancreatic cancer cells undergoing starvation and promotes GLI3-mediated VMP1 transcriptional activity. Thus, together these data provide evidence of a new regulatory mechanism modulating authophagy and integrates this cellular process into the network of events promoting pancreatic carcinogenesis.