Cigarette smoke condensate promotes cell proliferation through disturbance in cellular redox homeostasis of transformed lung epithelial type-II cells.
Present study was initiated to evaluate the effects of cigarette smoke condensate (CSC) on the cellular changes at molecular levels in non-small lung carcinoma cells (A549). Cigarette smoke condensate at low concentration (0.1 microg/ml) induced cancer cell proliferation, DNA synthesis, reduced glutathione (GSH) levels and intercellular adhesion molecule-1 (ICAM-1) expression without any significant change in reactive oxygen species (ROS) and superoxide radicals (SOR) production. The increased levels of GSH and ICAM-1 due to increased gamma-glutamylcysteine synthetase (gamma-GCS) activity and transcriptional activation of ICAM-1 gene respectively might be via activation of p38 mitogen activated protein kinase (p38 MAPK). The induction of ICAM-1 expression and cell proliferation reflect the tumor promoting activity of low CSC concentration. On the other hand, high CSC concentration (50 microg/ml), which is doubtful to be achieved in the lungs even in the chain smokers, induced killing effects on cancer cells by increasing apoptosis, ROS and SOR production, inducing cell cycle arrest, and increased ICAM-1 levels. These changes were found to be associated with altered GSH/GSSG ratio which shifted the redox balance towards more oxidizing equivalent followed by activation of p38 MAPK and stress-activated protein kinase (SAPK) involved in signaling cascade and finally transcriptional activation of gamma-GCS and ICAM-1 genes. These changes were found to be p38 and SAPK dependent.
Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Gaurav
G
Kaushik
Toshi
T
Kaushik
Suchit
S
Khanduja
Chander Mohan
CM
Pathak
Krishan Lal
KL
Khanduja
D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D053938:DNA Fragmentation; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D011123:Polyploidy; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012906:Smoke; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione