title: Akt kinase mediates the prosurvival effect of smoking compounds in pancreatic ductal cells.
abstract: OBJECTIVE
  Cigarette smoking is a major risk factor for pancreatic cancer (PaCa). However, the mechanisms of smoking-induced PaCa remain unknown. Here we investigated the effect of smoking compounds on cell death pathways in pancreatic ductal cells, precursors of PaCa.
  
  
  METHODS
  Human pancreatic ductal cells (HPDE6-c7) were cultured with cigarette smoke extract (CSE) or smoking compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Apoptosis and autophagy were assessed by DNA fragmentation and immunofluorescence, respectively.
  
  
  RESULTS
  Exposure to CSE or NNK decreased DNA fragmentation and up-regulated BclXL. Akt kinase was activated by smoking compounds through reactive oxygen species-dependent mechanism. Specifically, Akt activation was prevented by inhibition of nicotinamide adenine dinucleotide oxidase. Molecular or pharmacologic inhibitions of Akt prevented the antiapoptotic effect of smoking compounds. Smoking compounds stimulated rapid (1 hour) and transient activation of 5'-adenosine monophosphate-activated protein kinase and formation of autophagic vacuoles, indicating stimulation of autophagy. Repeated exposure to CSE/NNK (48 hours or longer) abolished the early activation of autophagic markers. Inhibition of Akt prevented the antiautophagic effect of long exposure to smoking compounds, indicating that smoking-induced late activation of Akt prevents autophagy.
  
  
  CONCLUSIONS
  Long exposure of pancreatic ductal cells to smoking compounds inhibited apoptosis and autophagy. The results revealed a central role for Akt kinase in mediating key procarcinogenic effects of smoking compounds.
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System and University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: In-Seok
authors.initials: IS
authors.lastname: Lee
authors.forename: Paul
authors.initials: P
authors.lastname: Grippo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
authors.forename: Mouad
authors.initials: M
authors.lastname: Edderkaoui
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity; D010183:Pancreatic Ducts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism* / Q000473:pathology*; D014026:Nicotiana / Q000633:toxicity; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002273:Carcinogens; D009602:Nitrosamines; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D012906:Smoke; D051020:bcl-X Protein; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000263:Adenylate Kinase