Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by β-carotene via activation of cAMP, PKA, CREB and ERK1/2

Abstract

An a-tocopherol, b-carotene supplementation trial (ATBC) and a chemoprevention trial with b-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 b-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 b-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 b-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 b-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 b-carotene may be useful as a cancer preventive agent. ' 2005 Wiley-Liss, Inc.Key words: b-carotene; human lung adenocarcinoma; signal transduction; growth stimulation Lung cancer is the leading cause of cancer deaths in industrialized countries.1-3 Among the 4 major types of lung cancer recognized by the WHO classification (adenocarcinoma, small cell carcinoma, squamous cell carcinoma, large cell carcinoma) pulmonary adenocarcinoma (PAC) predominates today, accounting for about 60% of all lung cancer cases. 2,4,5 Smoking is a welldocumented risk factor for all types of lung cancers 6,7 while a high fat diet constitutes an additional risk factor for PAC.8-10 Human PAC may be derived from bronchiolar Clara cells or from alveolar type II cells. Immunohistochemistry is primarily used to identify cell lineage of this cancer type by using antibodies to the Clara cell-specific CC10 protein and the alveolar type II cell-specific surfactant. Using this technique, PAC of Clara cell lineage has been reported to account for about 50% of the PAC cases.11 By contrast, electron microscopic investigations have identified 90% of PAC as being derived from Clara cells.12 Recent reports have shown that exposure to cigarette smoke or the tobaccospecific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) downregulate the expression of the Clara cell-speci...

Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention

“…The colorimetric 3-(4, 5-dimethyle thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay (Sigma) was performed as previously described [31] to assess the concentration dependence of inhibitory effects of GABA on cell proliferation. NSCLC cells were treated with GABA (0.5 µM to 128 µM) for 72 hours.…”

β-Carotene promotes the development of NNK-induced small airway-derived lung adenocarcinoma

“…In vitro studies in human small airway-derived PAC cells and small airway epithelia showed that l concentrations of 1 pM – 2 μM of beta-carotene, retinol, ATRA, 9-cis-RA or 13-cis-RA increased intracellular cAMP, activating PKA CREB and ERK1/2 (18, 19). These findings suggest that beta-carotene may promote small airway-derived PAC in vivo.…”

Suppression of Sebum Production and Accumulation by <i>β</i>-Cryptoxanthin Due to the Inhibition of the Expression of Diacylglycerol Acyltransferase-1 and Perilipin in Hamster Sebocytes

“…We previously reported that neither the level of cyclic AMP (cAMP) nor PKA activity was augmented by 13-cisRA [18], of which its suppressive action against sebum accumulation is similar to that of β-CRX in differentiated hamster sebocytes. However, β-carotene, which is structurally and functionally similar to β-CRX [39], has been reported to increase the level of cAMP and PKA activity in human pulmonary adenocarcinoma cells and epithelial cells from small airways and pancreatic ducts [40,41]. Thus, β-CRX may also influence the phosphorylation of PLIN1, which is coordinately associated with the abolishment of lipiddroplets in differentiated hamster sebocytes.…”