title: Glycogen synthase kinase 3 protein kinase activity is frequently elevated in human non-small cell lung carcinoma and supports tumour cell proliferation.
abstract: BACKGROUND
  Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC.
  
  
  METHODS
  The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture.
  
  
  RESULTS
  Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes.
  
  
  CONCLUSIONS
  NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom; Department of Physiology, McIntyre Building, McGill University, Montreal, Quebec, H3G 1Y6, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Douglas J E
authors.initials: DJ
authors.lastname: Elder
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Linda
authors.initials: L
authors.lastname: O'Flaherty
authors.affiliation: Department of Oncology, Hammersmith Campus, Cyclotron Building, London, W12 0NN, United Kingdom.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Piotr
authors.initials: P
authors.lastname: Dzien
authors.affiliation: Department of Respiratory Medicine, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom.
authors.forename: Lois
authors.initials: L
authors.lastname: Phillips
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Carys
authors.initials: C
authors.lastname: Morgan
authors.affiliation: Division of Histopathology, Bristol Royal Infirmary, Marlborough Street, Bristol, BS2 8HW, United Kingdom.
authors.forename: Joya
authors.initials: J
authors.lastname: Pawade
authors.affiliation: School of Social and Community Medicine, Canynge Hall, University of Bristol, 39 Whatley Road, Bristol, BS8 2PS, United Kingdom.
authors.forename: Margaret T
authors.initials: MT
authors.lastname: May
authors.affiliation: Division of Histopathology, Bristol Royal Infirmary, Marlborough Street, Bristol, BS2 8HW, United Kingdom.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sohail
authors.affiliation: Department of Respiratory Medicine, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Hetzel
authors.affiliation: Department of Oncology, Hammersmith Campus, Cyclotron Building, London, W12 0NN, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavaré
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D038362:Glycogen Synthase Kinase 3