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

PAPADEMETRIO D; LOMPARDIA S; SIMUNOVICH T; COSTANTINO S; MIHALEZ C; CAVALIERE V; ALVAREZ E

TARGETED ONCOLOGY

SPRINGER

Lugar: Berlin; Año: 2016 vol. 2016 p. 343 - 352

1776-2596

Background Pancreatic ductal adenocarcinoma (PDAC) is anaggressive disease with a survival rate of 4?6 months fromdiagnosis. PDAC is the fourth leading cause of cancer-relateddeath in the Western world, with a mortality rate of 10 casesper 100,000 population. Chemotherapy constitutes only a palliativestrategy, with limited effects on life expectancy.Aims To investigate the biological response of PDAC tomitogen-activated protein kinase (MAPK) and NF-kappaB(NF-kB) inhibitors and the role of autophagy in the modulationof these signaling pathways in order to address the challenge ofdeveloping improvedmedical protocols for patientswith PDAC.Methods Two ATCC cell lines, MIAPaCa-2 and PANC-1,were used as PDAC models. Cells were exposed to inhibitorsofMAPKor NF-kB survival pathways alone or after autophagyinhibition. Several aspects were analyzed, as follows: cell proliferation,by [3H]TdR incorporation; cell death, by TUNELassay, regulation of autophagy by LC3-II expression level andmodulation of pro-and anti-apoptotic proteins by Western blot.Results We demonstrated that the inhibition of theMAPK andNF-kB survival pathways with U0126 and caffeic acidphenethyl ester (CAPE), respectively, produced strong inhibitionof pancreatic tumor cell growth without inducing apoptoticdeath. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner inMIA PaCa-2 cells and in a caspase-independent manner inPANC-1 cells.Conclusions Here we present evidence that allows us to considera combined therapy regimen comprising an autophagyinhibitor and a MAPK or NF-kB pathway inhibitor as a possibletreatment strategy for pancreatic cancer.