title: Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells.
abstract: OBJECTIVE
  There are currently no targeted therapies against lung tumors with oncogenic K-ras mutations that are found in 25% to -40% of lung cancers and are characterized by their resistance to epidermal growth factor receptor inhibitors. The isozyme group IIa secretory phospholipase A(2) (sPLA(2)IIa) is a potential biomarker and regulator of lung cancer cell invasion; however, the relationship between K-ras mutations and sPLA(2)IIa has yet to be investigated. We hypothesize that sPLA(2)IIa modulates lung cancer cell growth in K-ras mutant cells and that sPLA(2)IIa expression in human lung tumors is increased in K-ras mutant tumors.
  
  
  METHODS
  Baseline sPLA(2)IIa expression in K-ras mutant lung cancer cell lines (A549, SW1573, H358, H2009) was assessed. Cells were treated with a specific sPLA(2)IIa inhibitor and evaluated for apoptosis and cell viability. Nuclear factor kappa-b (NF-κB) and extracellular signal-regulated kinase 1/2 activity were detected by Western blot. Human tumor samples were evaluated for sPLA(2)IIa mRNA expression by quantitative reverse-transcription polymerase chain reaction.
  
  
  RESULTS
  Cytotoxicity of sPLA(2)IIa inhibition correlates with sPLA(2)IIa expression. Apoptosis in response to sPLA(2) inhibition parallels attenuation in NF-κB activity. In addition, sPLA(2)IIa expression in human tumors correlates with squamous cell pathology and increasing stage of K-ras mutant lung tumors.
  
  
  CONCLUSIONS
  Baseline sPLA(2)IIa expression predicts response to sPLA(2)IIa inhibition in some K-ras mutant lung cancer cells. This finding is independent of p53 mutation status. Furthermore, squamous tumors and advanced-stage K-ras mutant tumors express more sPLA(2)IIa. These data support a role for sPLA(2)IIa as a potential global therapeutic target in the treatment of lung cancer.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, Colo 80045, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Yu
authors.forename: Howard
authors.initials: H
authors.lastname: Li
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Nemenoff
authors.forename: John D
authors.initials: JD
authors.lastname: Mitchell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins