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

CATRINACIO, C.; ALEJANDRO JAVIER ROPOLO; RODRIGUEZ, M. E.; MOLEJÓN, M. I.; ORQUERA, T.; RIVAROLA, V. A.; VACCARO, M. I.

Ciudad Autónoma de Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

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

process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in both tumor suppression and tumor progression. Tumor cells develop autophagy as an adaptation to stressful conditions such as hypoxia and treatment. VMP1 is a transmembrane protein necessary for autophagy induction. Previously, we demonstrated that the PI3K-AKT1 signaling pathway activates the GLI3-p300 complex that binds to the VMP1 promoter to regulate its activity in pancreatic tumor cells. Here we characterize new molecular pathways mediated by VMP1, by which gemcitabine, in human pancreatic tumor cells and hypoxia, in colon cancer cells, can trigger autophagy and resistance to treatment. We demonstrate that gemcitabine requires VMP1 expression to induce autophagy in highly resistant pancreatic cancer cells PANC-1 but not in less resistant BxPC-3 cells. Analysis of the mechanisms identified E2F1 as an effector of gemcitabine. We show that E2F1 regulates the expression and promoter activity of VMP1. Moreover, our study demonstrates that the pharmacological stabilization of HIF-1α significantly increases VMP1-related autophagy through binding to hypoxia responsive elements in VMP1 promoter. Moreover, HIF-1α-induced autophagy increases cell survival after photodynamic therapy of CaCo2and Sw480 cells. Chromatin immunoprecipitation assays showed that E2F1 and HIF-1 bind to the VMP1 promoter in PANC-1 and Caco2 cells, respectively. Finally, wedemonstrate that downregulation of VMP1 expression and pharmacological modulation of autophagy sensitize cells to antitumor treatments. We described two novel transcriptional regulation mechanisms of autophagy mediated by HIF-1α/VMP1 and E2F1/VMP1 pathways that may explain resistance in colon and pancreas adenocarcinomas. These findings are of high clinical relevance since they integrate VMP1-related autophagy to the complex network of events involved in tumor cell resistance.