Cyclic adenosine monophosphate-dependent cell type-specific modulation of mitogenic signaling by retinoids in normal and neoplastic lung cells.
BACKGROUND
Lung cancer is the leading cause of cancer death worldwide. A diet rich in fruit and vegetables has been shown to reduce the lung cancer risk. However, clinical trials with beta-carotene and retinoids have disappointed, resulted in increased mortality from lung cancer and cardiovascular disease.


METHODS
We have investigated the effects of the two major retinol metabolites, 9-cis-retinoic acid (9-Cis-RA), and 13-cis-retinoic acid (13-Cis-RA), on cell proliferation (MTT assays), intracellular cAMP (cAMP immunoassays), PKA activation (non-radioactive PKA activation assays), and ERK1/2 phosphorylation (Western blots) in immortalized human small airway epithelial cells, HPL1D, a human lung adenocarcinoma cell line, NCI-H322, immortalized human bronchial epithelial cells, BEAS-2B, and in the human small cell lung carcinoma cell line, NCI-H69.


RESULTS
Both retinoids increased intracellular cAMP and PKA activation in all cell lines. In BEAS-2B and NCI-H69 cells, the stimulation of cAMP/PKA reduced the phosphorylation of ERK1/2 and inhibited cell proliferation whereas phosphorylation of ERK1/2 and cell proliferation were increased in HPL1D and NCI-H322 cells.


CONCLUSIONS
Our data have identified a novel mechanism of action of 9-Cis-RA and 13-Cis-RA: activation of PKA in response to increased cAMP. The observed stimulation of cAMP/PKA may inhibit the development of small cell lung carcinoma and other tumors derived from large airway epithelia whereas it may selectively promote the development of lung tumors derived from small airway epithelial cells, such as adenocarcinoma.
Al-Wadei
Hussein A N
HA
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Schuller
Hildegard M
HM
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000077556:Alitretinoin; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D015474:Isotretinoin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000077556:Alitretinoin; D014212:Tretinoin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015474:Isotretinoin