VMP1-RELATED AUTOPHAGY CONFERS RESISTANCE TO TREATMENT AND HYPOXIA IN TUMOR CELLS FROM HUMAN GASTROINTESTINAL ADENOCARCINOMAS

TAMARA ORQUERA; CINTIA BETIANA CATRINACIO; MARÍA INÉS VACCARO; ALEJANDRO ROPOLO

CABA

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC, SAIB, SAI, SAA, SAB, SAB, SAFE, SAFIS, SAH, SAP

Autophagy is an evolutionarily conserved degradationprocess of cytoplasmic cellular constituents. It has beensuggested that autophagy plays a role in both tumor suppressionand tumor progression. Tumor cells developautophagy as an adaptation to stressful conditions suchas hypoxia and treatment. VMP1 is a transmembraneprotein necessary for autophagy induction. Previously,we demonstrated that the PI3K-AKT1 signaling pathwayactivates the GLI3-p300 complex that binds to the VMP1promoter to regulate its activity in pancreatic tumor cells.Here we characterize new molecular pathways mediatedby VMP1, by which gemcitabine, in human pancreatic tumorcells and hypoxia, in colon cancer cells, can triggerautophagy and resistance to treatment. We demonstratethat gemcitabine requires VMP1 expression to induceautophagy in highly resistant pancreatic cancer cellsPANC-1 but not in less resistant BxPC-3 cells. Analysisof the mechanisms identified E2F1 as an effector ofgemcitabine. We show that E2F1 regulates the expressionand promoter activity of VMP1. Moreover, our studydemonstrates that the pharmacological stabilization ofHIF-1α significantly increases VMP1-related autophagythrough binding to hypoxia responsive elements in VMP1promoter. Moreover, HIF-1α-induced autophagy increasescell survival after photodynamic therapy of CaCo2and Sw480 cells. Chromatin immunoprecipitation assaysshowed that E2F1 and HIF-1 bind to the VMP1 promoterin PANC-1 and Caco2 cells, respectively. Finally, wedemonstrate that downregulation of VMP1 expressionand pharmacological modulation of autophagy sensitizecells to antitumor treatments. We described two noveltranscriptional regulation mechanisms of autophagy mediatedby HIF-1α/VMP1 and E2F1/VMP1 pathways thatmay explain resistance in colon and pancreas adenocarcinomas.These findings are of high clinical relevancesince they integrate VMP1-related autophagy to the complexnetwork of events involved in tumor cell resistance.