title: Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy.
abstract: BACKGROUND
  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4-6 months from diagnosis. PDAC is the fourth leading cause of cancer-related death in the Western world, with a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on life expectancy.
  
  
  OBJECTIVE
  To investigate the biological response of PDAC to mitogen-activated protein kinase (MAPK) and NF-kappaB (NF-kB) inhibitors and the role of autophagy in the modulation of these signaling pathways in order to address the challenge of developing improved 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, as follows: cell proliferation, by [(3)H]TdR incorporation; cell death, by TUNEL assay, regulation of autophagy by LC3-II expression level and modulation of pro-and anti-apoptotic proteins by Western blot.
  
  
  RESULTS
  We demonstrated that the inhibition of the MAPK and NF-kB survival pathways with U0126 and caffeic acid phenethyl ester (CAPE), respectively, produced strong inhibition of pancreatic tumor cell growth without inducing apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIA PaCa-2 cells and in a caspase-independent manner in PANC-1 cells.
  
  
  CONCLUSIONS
  Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. dpapademetrio@ffyb.uba.ar.|IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. dpapademetrio@ffyb.uba.ar.
authors.forename: Daniela Laura
authors.initials: DL
authors.lastname: Papademetrio
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.|IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Silvina Laura
authors.initials: SL
authors.lastname: Lompardía
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Tania
authors.initials: T
authors.lastname: Simunovich
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.|IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Susana
authors.initials: S
authors.lastname: Costantino
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.|IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Cintia Yamila
authors.initials: CY
authors.lastname: Mihalez
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cavaliere
authors.affiliation: Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. elialv@ffyb.uba.ar.|IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina. elialv@ffyb.uba.ar.
authors.forename: Élida
authors.initials: É
authors.lastname: Álvarez
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D002109:Caffeic Acids; D016328:NF-kappa B; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol