VMP1 is a novel target gene required for HIF-1a-induced autophagy in pancreatic cancer cell.

CATRINACIO, C.; VACCARO, M. I.; ALEJANDRO JAVIER ROPOLO

Sendai

Congreso; 20th International Association of Pancreatology (IAP), 47th Japan Pancreas Society (JPS) and 6th Asian Oceanic Pancreatic Association (AOPA) Meeting; 2016

International Association of Pancreatology

Autophagy is an evolutionary preserved degradation process of cytoplasmic cellular constituents, which participates in cell response to disease. We characterized VMP1 (Vacuole Membrane Protein 1) as an essential autophagy related protein that mediates autophagy in pancreatic diseases. Hypoxia is a common feature in solid tumor and leads to treatment resistance. Recently, it has been shown that in response to hypoxia, cancer cells can induce HIF1amediated autophagy to survive in its hostile micro environment. However, the molecular signals by which HIF1a induces autophagy are not completely understood. Therefore, we evaluated the role of HIF1a and autophagy as well as the underlying mechanism in the survival of pancreatic cancer cells. We used cobalt chloride (CoCl2) as a chemical hypoxia-mimicking agent. Using specifics siRNA strategies, methods for autophagy detection and chromatin immunoprecipitation assays, we demonstrate that, under hypoxia mimic, HIF1a significantly augmented VMP1related autophagy through its binding to hypoxia-responsive elements on VMP1 promoter. Furthermore, using cell proliferation and clonogenic assays we found that HIF1aVMP1-mediated autophagy is able to increase cell survival of PANC-1 and MiaPaCa-2 cells undergoing hypoxia. Also, we show that the inhibition of autophagy, by 3MA or VMP1 reduced expression, decreases cell survival after the induction of chemical hypoxia, suggesting that hypoxia induces autophagy as a survival mechanism. In conclusion, survival of pancreatic cancer cells under hypoxia may be explained by the induction of the novel HIF1a/VMP1/autophagy pathway. These data provide evidence of a transcriptional regulation under hypoxia that integrates autophagy into the complex network of events involved in pancreatic cancer cell resistance.