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Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids.

ABSTRACT: SCOPE:The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1?,25-dihydroxyvitamin D3 (1?,25(OH)2 D3), lithocholic acid, curcumin, nicotinamide, and butyrate. Discovering additional small molecules that regulate its expression will identify new molecular mechanisms involved in CAMP regulation and increase understanding of how diet and nutrition can improve immune function. METHODS AND RESULTS:We discovered that two stilbenoids, resveratrol and pterostilbene, induced CAMP promoter-luciferase expression. Synergistic activation was observed when either stilbenoid was combined with 1?,25(OH)2 D3. Both stilbenoids increased CAMP mRNA and protein levels in the monocyte cell line U937 and synergy was observed in both U937 and the keratinocyte cell line, HaCaT. Inhibition of resveratrol targets sirtuin-1, cyclic AMP production and the c-Jun N-terminal, phosphoinositide 3 and AMP-activated kinases did not block induction of CAMP by resveratrol or synergy with 1?,25(OH)2 D3. Nevertheless, inhibition of the extracellular signal regulated 1/2 and p38 mitogen-activated protein kinases, increased CAMP gene expression in combination with 1?,25(OH)2 D3 suggesting that inhibition of these kinases by resveratrol may explain, in part, its synergy with vitamin D. CONCLUSION:Our findings demonstrate for the first time that stilbenoid compounds may have the potential to boost the innate immune response by increasing CAMP gene expression, particularly in combination with 1?,25(OH)2 D3.

SUBMITTER: Guo C

PROVIDER: S-EPMC3947465 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids.

Guo Chunxiao C Sinnott Brian B Niu Brenda B Lowry Malcolm B MB Fantacone Mary L ML Gombart Adrian F AF

Molecular nutrition & food research 20130914 3

<h4>Scope</h4>The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2 D3), lithocholic acid, curcumin, nicotinamide, and butyrate. Discovering additional small molecules that regulate its expression will identify new molecular mechanisms involved in CAMP regulation and increase understanding of how diet and nutrition can improve immune function.<h4>Methods and results</h4>We discovered that two stilbenoids, resveratrol and pterostilbene, induced CAM ...[more]

PMID: 24039193

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Project description:BackgroundIn normal and neoplastic cells, growth-promoting, proangiogenic, cytotoxic and pro-apoptotic effects have all been attributed to cathelicidin antimicrobial peptide (CAMP). Nevertheless, little is known about the factors regulating this peptide expression in breast cancer. Herein we asked if the well-known antineoplastic hormone calcitriol could differentially modulate CAMP gene expression in human breast cancer cells depending on the cell phenotype in terms of efficacy and potency.MethodsThe established breast cancer cell lines MCF7, BT-474, HCC1806, HCC1937, SUM-229PE and a primary cell culture generated from invasive ductal breast carcinoma were used in this study. Calcitriol regulation of cathelicidin gene expression in vitro and in human breast cancer xenografts was studied by real time PCR. Tumorigenicity was evaluated for each cell line in athymic mice.ResultsEstrogen receptor (ER)α + breast cancer cells showed the highest basal CAMP gene expression. When incubated with calcitriol, CAMP gene expression was stimulated in a dose-dependent and cell phenotype-independent manner. Efficacy of calcitriol was lower in ERα + cells when compared to ERα- cells (<10 vs. >70 folds over control, respectively). Conversely, calcitriol lowest potency upon CAMP gene expression was observed in the ERα-/EGFR+ SUM-229PE cell line (EC50 = 70.8 nM), while the highest was in the basal-type/triple-negative cells HCC1806 (EC50 = 2.13 nM) followed by ERα + cells MCF7 and BT-474 (EC50 = 4.42 nM and 14.6 nM, respectively). In vivo, lower basal CAMP gene expression was related to increased tumorigenicity and lack of ERα expression. Xenografted triple-negative breast tumors of calcitriol-treated mice showed increased CAMP gene expression compared to vehicle-treated animals.ConclusionsIndependently of the cell phenotype, calcitriol provoked a concentration-dependent stimulation on CAMP gene expression, showing greater potency in the triple negative HCC1806 cell line. Efficacy of calcitriol was lower in ERα + cells when compared to ERα- cells in terms of stimulating CAMP gene expression. Lower basal CAMP and lack of ERα gene expression was related to increased tumorigenicity. Our results suggest that calcitriol anti-cancer therapy is more likely to induce higher levels of CAMP in ERα- breast cancer cells, when compared to ERα + breast cancer cells.

Dataset Information

Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids.

Publications

Synergistic induction of human cathelicidin antimicrobial peptide gene expression by vitamin D and stilbenoids.

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