title: p38 Mitogen-activated protein kinase signaling, ERCC1 expression, and viability of lung cancer cells from never or light smoker patients.
abstract: BACKGROUND
  Expression of DNA-repair proteins and activated mitogen-activated protein kinases (MAPKs) may differ according to smoking status. The authors investigated whether p38 MAPK activity contributed to the viability of cisplatin in lung cancer cell lines from never or light smokers and to ERCC1 mRNA expression.
  
  
  METHODS
  Activated p38 MAPK was tested as a predictor for ERCC1 levels in 117 lung adenocarcinomas. Cell viabilities of NCI-H1975, NCI-H1793, NCI-H1650, and NCI-H1651 cell lines, derived from never or light smokers, were measured after treatment with the p38 MAPK inhibitor SB202190 and cisplatin. The role of p38α (MAPK14) and p38β (MAPK11) isoforms and ERCC1 was evaluated using RNA interference.
  
  
  RESULTS
  ERCC1 protein-level expression was predicted by activated p38 MAPK in lung adenocarcinoma tissues. The p38-specific inhibitor SB202190 strongly decreased cell viability (43%-63%). SB202190 plus cisplatin significantly decreased cell viability in every cell line, including cisplatin-resistant NCI-H1793. Genetic inhibition, targeting both MAPK11 and MAPK14, reduced the viability of the different cell lines: down-regulation of p38β accounted for most of this effect. Cisplatin's effect was greater after MAPK11 down-regulation for NCI-H1651, and MAPK14 down-regulation for NCI-H1650. In addition, both SB202190 and MAPK11 inhibition reduced excision repair cross-complementing 1 mRNA levels.
  
  
  CONCLUSIONS
  Lung cancer cells from never or light smokers rely on p38 MAPK signaling for survival. MAPK11 is involved in that pathway and might contribute to ERCC1 expression. Sensitization to cisplatin can be achieved by pharmacological inhibition of p38 MAPK signaling.
authors.affiliation: French Institute of Health and Medical Research U981 Thoracic Unit, Gustave Roussy Institute, Villejuif, France. david.planchard@igr.fr
authors.forename: David
authors.initials: D
authors.lastname: Planchard
authors.forename: Valérie
authors.initials: V
authors.lastname: Camara-Clayette
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dorvault
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D012907:Smoking; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin