Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2.
An alpha-tocopherol, beta-carotene supplementation trial (ATBC) and a chemoprevention trial with beta-carotene and retinoids (CARET trial) were conducted in the 1990s in populations at risk for the development of lung cancer. Both trials had to be discontinued due to significant increases in lung cancer and cardiovascular mortality. Clinical trials to test the cancer preventive effects of beta-carotene are still ongoing, and high concentrations of this provitamin are contained in numerous dietary supplements. Using a cell line derived from a human pulmonary adenocarcinoma (PAC) of Clara cell lineage and immortalized human small airway epithelial cells, our data show that low concentrations of beta-carotene that can be realistically expected in human tissues after oral administration caused a significant increase in intracellular cAMP and activated PKA, as well as in phosphorylation of ERK1/2 and CREB. Furthermore, the proliferation of cells was significantly stimulated by identical concentrations of beta-carotene as monitored by MTT assays. Control experiments with retinol also showed stimulation of cell proliferation and activation of PKA in both cell lines. In light of the fact that PAC is the leading type of lung cancer, these findings suggest that the growth promoting effects of beta-carotene on this cancer type observed in our experiments may have contributed to the unfortunate outcome of the ATBC and CARET trials. This interpretation is supported by the fact that elevated levels of cAMP in the cardiovascular system play a major role in the genesis of cardiovascular disease, which was also greatly promoted in the CARET trial. Our data challenge the widely accepted view that beta-carotene may be useful as a cancer preventive agent.
Al-Wadei
Hussein A N
HA
Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
Takahashi
Takashi
T
Schuller
Hildegard M
HM
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014815:Vitamins / Q000494:pharmacology; D019207:beta Carotene / Q000494:pharmacology*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D014815:Vitamins; D019207:beta Carotene; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3