Reduced DNA-dependent protein kinase activity is associated with lung cancer.
Reduced DNA repair capacity of carcinogen-induced DNA damage is now thought to significantly influence inherent susceptibility to lung cancer. DNA-dependent protein kinase (DNA-PK) is a serine-threonine kinase activated by the presence of double-strand breaks in DNA that appears to play a major role in non-homologous recombination and transcriptional control. The purpose of this study was to determine whether DNA-PK activity varies among individuals and how this affects lung cancer risk. DNA-PK activity in peripheral mononuclear cells from individuals with lung cancer (n = 41) was compared with lung cancer-free controls (n = 41). Interindividual variability was seen within each group, however, significant differences (P = 0.03) in DNA-PK activity between cases and controls were seen when comparing the distribution of enzyme activity among these two groups. The percentages of cases and controls with DNA-PK activity in the ranges 2.5-5.0 and 7.6-10.0 units were 39 versus 20% and 7 versus 29%, respectively. The enzyme activity in peripheral mononuclear cells reflected that seen in bronchial epithelial cells, one progenitor cell for lung cancer, supporting the use of peripheral mononuclear cells for larger population-based studies of DNA-PK activity. Its role as a potential modifier for lung cancer risk was supported by the fact that cell growth in bronchial epithelial cells exposed to bleomycin was directly associated with enzyme activity. The results of this study demonstrate that reduced DNA-PK repair activity is associated with risk for lung cancer.
Auckley
D H
DH
Division of Pulmonary, Critical Care and Allergy, University of New Mexico and the New Mexico Veterans Health Care System, Albuquerque, NM 87108, USA.
Crowell
R E
RE
Heaphy
E R
ER
Stidley
C A
CA
Lechner
J F
JF
Gilliland
F D
FD
Belinsky
S A
SA
D000328:Adult; D000368:Aged; D001761:Bleomycin / Q000494:pharmacology; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D001761:Bleomycin; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases