Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy

PAPADEMETRIO D. L.; LOMPARDÍA S. L.; SIMUNOVICH T. C.; COSTANTINO S.; MIHALEZ C.Y.; CAVALIERE V.; ALVAREZ E. M. C.

TARGETED ONCOLOGY

SPRINGER

Lugar: Berlin; Año: 2016

1776-2596

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4-6 months from the diagnosis. PDAC is the fourth leading cause of death among cancers in the western world. This incidence has a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on 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, results 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 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 Phenethyl 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 allows us to consider a combined therapy of an inhibitor of autophagy with an nhibitor of MAPK or NF-kB pathways, as a possible treatment regimen for pancreatic cancer.