Inhibition of survival pathways, MAPK and NF-kB, trigger apoptosis in pancreatic ductal adenocarcinoma cells via suppression of autophagy

DANIELA LAURA PAPADEMETRIO; SUSANA COSTANTINO; ÉLIDA ÁLVAREZ; SILVINA LAURA LOMPARDÍA; CINTIA YAMILA MIHALEZ; TANIA SIMUNOVICH; DANIELA LAURA PAPADEMETRIO, ALDANA TRABUCCHI, VICTORIA CAVALIERE, RAFAEL RICCO, SUSANA COSTANTINO, MARCELO LUIS WAGNER, ELIDA ÁLVAREZ.

TARGETED ONCOLOGY

SPRINGER

Lugar: Berlin; Año: 2016

1776-2596

AbstractBackground: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4-6 month since the diagnosis. PDAC is the fourth leading cause of death among cancers in the western world. This incidence has a mortality rate of 10 out of every 100,000 cases. Chemotherapy constitutes only a palliative strategy, with limited effects on the life expectancy. Aims: To investigate the biological response of PDAC to MAPK and NF-kB inhibitors and the role of autophagy in the modulation of these signaling pathways result in a challenging work in order to improve medical protocols for patients with PDAC.Methods: Two ATCC cell lines, MIAPaCa-2 and PANC-1, were used as PDAC models. Cells were exposed to inhibitors of MAPK or NF-kB survival pathways alone or after autophagy inhibition. Several aspects were analyzed, cell proliferation, by [3H]TdR incorporation, cell death, assayed by subG1 peak and TUNEL, regulation of autophagy by LC3-II level expression and modulation of pro-and anti-apoptotic proteins by western blot.Results: We demonstrated that the inhibition of survival pathways MAPK and NF-kB, with U0126 and CAPE (caffeic acid phenylethyl ester), respectively, produced a strong inhibition of pancreatic tumor cells growth, without induction of apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIAPaCa-2 cells and in a caspase-independent way in PANC-1 cells.Conclusions: Here, we present evidence that permit consider a combine therapy of an inhibitor of autophagy with an inhibitor of MAPK or NF-kB pathways, as a possible treatment regimen for pancreatic cancer.