Vacuole-Membrane-Protein-1 (VMP1) Mediated-autophagy Correlates with Loss of p21 Expression in Human Pancreatic Cancer

ALEJANDRO JAVIER ROPOLO; LOZANO-LEON, A.; BOGGIO, V.; DOMINGUEZ-MUÑOZ, E.; VACCARO, M.I.

Estocolmo

Congreso; 42nd European Pancreatic Club (EPC) Meeting; 2010

European Pancreatic Club

Introduction: VMP1 is a pancreatitis-induced protein whose expression triggers autophagy. We previously showed that VMP1-autophagy pathway promotes apoptosis in pancreatic cancer cells. Objectives: Here, we evaluate the expression of VMP1 and its relationship with p21 and p53 in human pancreatic ductal-adenocarcinoma. We also investigated LC3 expression as a marker of autophagy. Materials and Methods: Tissue microarrays were performed from tumor stage advanced; 50-pancreatic cancer and 7-control samples were included. Results: Immunohistochemistry revealed VMP1 expression in glandular cells in 10 (20%) of the tumor samples but none in controls. The same expression pattern was observed for LC3, suggesting VMP1-mediated autophagy. Tumor samples also showed loss expression of p21, which correlated with VMP1 (p < 0.001) and p53 (p < 0.03) were observed. Interestingly, patient?s survival was higher in VMP1-expressing pancreatic cancer samples. In order to analyze the pathological role of the VMP1 and p21 relationship in tumor cells, we used HCT116 and HCT116 p21-/- cells. VMP1 expression was higher in p21-/- cells that showed autophagy activation evidenced by the recruitment of LC3. Flow cytometry of annexin V revealed significant reduction of apoptotic levels in HCT116 p21-/- cells after starvation-induced autophagy. Contrary, overexpression of VMP1 in HCT116 cells showed significant increase of apoptosis after autophagy induction. Conclusion: Our results demonstrate that p21 expression allows apoptosis in tumor cells undergoing VMP1-mediated autophagy and the loss of p21 reduces apoptosis and favors autophagy, disassembling VMP1-mediated autophagy from apoptosis. We propose that VMP1 and p21 expression are involved in the crosstalk between autophagy and apoptosis in human pancreatic cancer.