Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke

Our plain-English summary of Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke, by X.D. Wang, C. Liu, R.T. Bronson, et al (Journal of the National Cancer Institute, 1999).

The study

• Authors: X.D. Wang, C. Liu, R.T. Bronson, D.E. Smith, N.I. Krinsky, M. Russell
• Journal: Journal of the National Cancer Institute
• Published: 1999;91(1):60-6
• Cited by: 265 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Epidemiologic studies have demonstrated that individuals who eat more fruits and vegetables and/or have high levels of serum beta-carotene have a lower risk of cancer, especially lung cancer. However, recent human intervention studies using beta-carotene supplements have shown an increase in the risk of lung cancer among smokers and asbestos workers. In this study, we used an animal model system to evaluate the hazard associated with a combination of high-dose beta-carotene supplementation and tobacco smoking.

Methods: Ferrets were given a beta-carotene supplement, exposed to cigarette smoke, or both for 6 months. Cell proliferation and squamous metaplasia in lung tissue were assessed by examination of proliferating-cell nuclear antigen expression and histopathologic examination, respectively. beta-Carotene and retinoid concentrations in lung tissue and plasma samples were analyzed by high-performance liquid chromatography. Expression of genes for retinoic acid receptors (RARs) and activator protein-1 (encoded by the c-Jun and c-Fos genes) in lung tissue specimens was examined by western blotting.

Results: A strong proliferative response in lung tissue and squamous metaplasia was observed in all beta-carotene-supplemented animals, and this response was enhanced by exposure to tobacco smoke. When compared with control groups, all three treatment groups had statistically significantly lower concentrations of retinoic acid in lung tissue, and they exhibited 18%-73% reductions in RARbeta gene expression; however, RARalpha and RARgamma gene expression was not reduced. Ferrets given a beta-carotene supplement and exposed to tobacco smoke had threefold to fourfold elevated expression of the c-Jun and c-Fos genes.

Conclusions: Diminished retinoid signaling, resulting from the suppression of RARbeta gene expression and overexpression of activator protein-1, could be a mechanism to enhance lung tumorigenesis after high-dose beta-carotene supplementation and exposure to tobacco smoke.

In plain English

This laboratory experiment in ferrets did not study asbestos. Asbestos appears only in the background: the authors cite an earlier human trial, which gave beta-carotene combined with vitamin A, that found more lung cancer among smokers and asbestos workers. Twenty-four male ferrets were randomly assigned to four groups of six for 6 months: cigarette smoke, high-dose beta-carotene, both, or neither. Squamous metaplasia, a lung change the authors call precancerous, was found in all six ferrets given beta-carotene alone and all six given beta-carotene plus smoke. It was found in none of the smoke-only or control ferrets. A marker of cell proliferation (PCNA) rose 1.8-fold with beta-carotene alone and 3.7-fold with both. Lung retinoic acid was significantly lower in all three treated groups than in controls, and RAR-beta receptor expression fell by 18% to 73%. Expression of c-Jun and c-Fos, measured by western blotting, was threefold to fourfold higher in the combined group than in controls. The authors concluded that one possible mechanism of harm in smokers was smoke-enhanced oxidation of beta-carotene.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: ferrets randomly assigned to four treatment groups for 6 months
• Who was studied: 24 male adult ferrets (1.0 to 1.2 kg) from Marshall Farms, North Rose, NY, housed at the Human Nutrition Research Center on Aging at Tufts University; six ferrets per group; dates not stated
• Exposure: Cigarette smoke (10 cigarettes over 30 minutes, twice in the morning and twice in the afternoon), high-dose beta-carotene (2.4 mg per kg per day, which the authors calculated as equivalent to 30 mg per day in a 70-kg human), both, or neither, for 6 months. No asbestos exposure was studied.
• Main results:
  • Keratinized squamous epithelium (squamous metaplasia) was observed in all six ferrets given high-dose beta-carotene alone
  • Squamous metaplasia was found in six of six ferrets given smoke plus high-dose beta-carotene, compared with none of six smoke-only ferrets and none of six untreated controls
  • PCNA expression (a measure of cell proliferation) in the lungs increased 3.7-fold in beta-carotene-supplemented ferrets exposed to smoke and 1.8-fold in beta-carotene-supplemented ferrets not exposed to smoke
  • Retinoic acid concentration in lung tissue was significantly lower in all three treatment groups than in the control group
  • Plasma retinoids (retinoic acid, retinol and retinyl palmitate) did not differ among the four groups
  • Compared with controls, RAR-beta expression in the lung was reduced by 18% to 73% across the three treatment groups (18% smoke-exposed, 62% high-dose beta-carotene, 73% both); RAR-alpha and RAR-gamma expression was not reduced
  • Expression of c-Jun and c-Fos (activator protein-1), assessed by western blotting, was threefold to fourfold higher in ferrets given beta-carotene and exposed to smoke than in controls
• The authors' conclusion: The authors concluded that one possible mechanism for the harmful effect of beta-carotene supplementation in smokers is that the free-radical-rich environment of smokers' lungs enhances beta-carotene oxidation. They proposed that the resulting metabolites might weaken retinoid signaling (lower RAR-beta and lung retinoic acid, higher activator protein-1) and so accelerate lung tumor development.
• Limitations the authors state:
  • The authors note that the associations of activator protein-1 overexpression with squamous metaplasia, PCNA and RAR-beta were not strong in ferrets given beta-carotene alone

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Tumorigenesis.

Related studies

• Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets — A. Fuster, C. Picó, et al. (2008)
• Effects of cigarette smoke and asbestos on airway, vascular and mesothelial cell proliferation — H. Sekhon, J. Wright, et al. (1995)
• beta-Carotene fails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Sencar mice — R.M. Ponnamperuma, Y. Shimizu, et al. (2000)
• Cigarette smoke makes airway and early parenchymal asbestos-induced lung disease worse in the guinea pig — V. Tron, J.L. Wright, et al. (1987)
• Tobacco-borne siderophoric activity — M.W. Qian, J.W. Eaton (1989)
• Cigarette smoke, asbestos, and small irregular opacities — W. Weiss (1984)

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