Gemcitabine requires E2F1-p300-VMP1 pathway to induce autophagy in human pancreatic tumor cells.

VACCARO MI

Southampton

Congreso; EPC/IAP Joint Meeting 2014; 2014

European Pancreatic Club and International Association of Pancreatology

EPC-IAP Abstract Topics Basic sciences:Genetics and epigenetics of pancreatic diseases Gemcitabine requires E2F1-p300-VMP1 pathway to induce autophagy in human pancreatic tumor cells. Ropolo A, Molejon MI, Renna F, Catrinacio C, Boggio V, Gonzalez C D, Vaccaro MI. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. Gemcitabine, a deoxycytidine analog, has become the standard chemotherapy for the treatment of advanced pancreatic cancer despite its poor efficacy because the relatively refractory of human pancreatic tumor cells. Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in both tumor suppression and tumor progression. Here we characterize a new molecular pathway, mediated by VMP1, an autophagy-related protein, by which gemcitabine is able to trigger autophagy in human pancreatic tumor cells. We demonstrated that Gemcitabine requires VMP1 expression to induce autophagy. Gemcitabine treatment induces early expression of VMP1 and autophagy in highly resistant pancreatic cancer cells PANC-1.  Analysis of the mechanisms identified E2F1, a transcription factor that is regulated by the retinoblastoma pathway, as an effector of gemcitabine-induced autophagy. E2F1 regulates the expression and promoter activity of VMP1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the VMP1 promoter. We also identified the histone acetyltransferase p300 as a modulator of this promoter activity.  Our data show that the E2F1-p300 activator/co-activator complex is part of the regulatory pathway controlling the expression and promoter activity of VMP1 triggered by gemcitabine. Finally, downregulation of VMP1 expression and pharmacological modulation of autophagy sensitize PANC-1 cells to apoptosis and diminish clonogenicity under gemcitabine treatment. Together, these data provide evidence of a transcriptional regulation mechanism of autophagy that integrates this cellular process into the complex network of events involved in PDAC chemoresistance.