The IAP Family Member BIRC5/Survivin Confers Resistance to Pancreas Cancer Cells by Autophagy Pathway Modulation

DANIEL GRASSO; MARIA NOÉ GARCIA; NADIA PAGLILLA; ELIDA ALVAREZ; MARTÍN LEVERMANN; DANIELA L. PAPADEMETRIO

Mar del Plata

Congreso; S A I C . S A F E . S A B . SAP 2 0 1 9; 2019

Sociedad Argentina de Investigación Clínica

Pancreatic ductal adenocarcinoma (PDAC) is a deadly and highly aggressive cancer. Gemcitabine (standard chemotherapy for PDAC) induces low levels of apoptosis as consequence that it is partially blocked by the autophagy induced during the treatment. Autophagy inhibition allows apoptosis triggered by inhibitors of MAPKs or NFkB pathway. In this context, a relationship between the Baculoviral IAP Repeat-Containing Protein 5 (BIRC5/Survivin), from IAPs family, and autophagy is observed.The aim of this work was to evaluate the modulation apoptosis-autophagy mediated by Survivin. By western blot, an increase of Survivin is observed in PDAC cell lines in response to the MAPKs inhibitor UO126. This increase is lessened by the autophagy inhibitor 3MA. Using a specific shRNA against Survivin, it is possible to observe, by TUNEL assay, the Survivin dependence of apoptosis induced by UO126. Moreover, this survivin-dependent cell death resistance is mediated by autophagy. Morphologically, Survivin have a moderated partial colocalization with the autophagy marker LC3 at basal condition which is increased by starvation. Interestingly, under the blockade of autophagy finalization steps, by chloroquine, Survivin accumulates in a nuclear proximity area where it colocalize with LC3 in close relationship to omegasome. In conclusion, Survivin is a key factor in PDAC cells resistance to treatment within an intricate mechanism with the autophagy pathway.