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Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation.

Bermudez Y, Benavente CA, Meyer RG, Coyle WR, Jacobson MK, Jacobson EL - PLoS ONE (2011)

Bottom Line: Receptor transcripts are greatly over-expressed in squamous cell cancers.In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling.The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Arizona Cancer Center and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT

Background: Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein-coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells.

Results: Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.

Conclusions: The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.

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Related in: MedlinePlus

Nicotinic acid promotes epidermal differentiation in photodamaged human skin.Tissue arrays of skin biopsy samples from a clinical study of the effects of myristyl nicotinate (MN) in human subjects with photodamaged skin [5] were stained for the terminal differentiation markers caspase 14 and filaggrin. Panel A: An example of a biopsy sample at baseline and 12 weeks of MN treatment stained with H&E, and immunostaining for caspase 14 or filaggrin. Panel B: Quantification of staining for the placebo (n = 27) and MN treated (n = 31) groups for caspase 14 and filaggrin. Students t-test was used to compare placebo and MN treated groups and p values are shown.
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pone-0020487-g001: Nicotinic acid promotes epidermal differentiation in photodamaged human skin.Tissue arrays of skin biopsy samples from a clinical study of the effects of myristyl nicotinate (MN) in human subjects with photodamaged skin [5] were stained for the terminal differentiation markers caspase 14 and filaggrin. Panel A: An example of a biopsy sample at baseline and 12 weeks of MN treatment stained with H&E, and immunostaining for caspase 14 or filaggrin. Panel B: Quantification of staining for the placebo (n = 27) and MN treated (n = 31) groups for caspase 14 and filaggrin. Students t-test was used to compare placebo and MN treated groups and p values are shown.

Mentions: Chronic UV exposure leads to impaired epidermal differentiation and increased epidermal proliferation that can result in actinic keratosis lesions and squamous cell cancers of the skin [19]. We have previously concluded that myristyl nicotinate (MN), a prodrug that delivers nicotinic acid to skin, promotes epidermal differentiation with associated enhanced skin barrier function in chronically photodamaged skin as judged by changes in epidermal and stratum corneum thickness, decreased rates of transepidermal water loss and increases in minimal erythemal dose [5]. To examine effects of MN on differentiation more directly, two epidermal differentiation markers, caspase 14 and filaggrin [20] were assessed in subjects with skin photodamage in a placebo controlled clinical trial [5]. Fig. 1A shows an example of biopsy samples stained at baseline and after 12 weeks of topical application of a formulation containing 5% MN and Fig. 1B shows quantification of caspase 14 and filaggrin in subjects treated with placebo or MN formulations. The presence of MN results in an increase relative to placebo of approximately 30% for caspase 14 and 20% for filaggrin. The placebo formulation substituted myristyl myristate for MN, ruling out any effects of myristyl alcohol that is generated as nicotinic acid is liberated from the prodrug.


Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation.

Bermudez Y, Benavente CA, Meyer RG, Coyle WR, Jacobson MK, Jacobson EL - PLoS ONE (2011)

Nicotinic acid promotes epidermal differentiation in photodamaged human skin.Tissue arrays of skin biopsy samples from a clinical study of the effects of myristyl nicotinate (MN) in human subjects with photodamaged skin [5] were stained for the terminal differentiation markers caspase 14 and filaggrin. Panel A: An example of a biopsy sample at baseline and 12 weeks of MN treatment stained with H&E, and immunostaining for caspase 14 or filaggrin. Panel B: Quantification of staining for the placebo (n = 27) and MN treated (n = 31) groups for caspase 14 and filaggrin. Students t-test was used to compare placebo and MN treated groups and p values are shown.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105069&req=5

pone-0020487-g001: Nicotinic acid promotes epidermal differentiation in photodamaged human skin.Tissue arrays of skin biopsy samples from a clinical study of the effects of myristyl nicotinate (MN) in human subjects with photodamaged skin [5] were stained for the terminal differentiation markers caspase 14 and filaggrin. Panel A: An example of a biopsy sample at baseline and 12 weeks of MN treatment stained with H&E, and immunostaining for caspase 14 or filaggrin. Panel B: Quantification of staining for the placebo (n = 27) and MN treated (n = 31) groups for caspase 14 and filaggrin. Students t-test was used to compare placebo and MN treated groups and p values are shown.
Mentions: Chronic UV exposure leads to impaired epidermal differentiation and increased epidermal proliferation that can result in actinic keratosis lesions and squamous cell cancers of the skin [19]. We have previously concluded that myristyl nicotinate (MN), a prodrug that delivers nicotinic acid to skin, promotes epidermal differentiation with associated enhanced skin barrier function in chronically photodamaged skin as judged by changes in epidermal and stratum corneum thickness, decreased rates of transepidermal water loss and increases in minimal erythemal dose [5]. To examine effects of MN on differentiation more directly, two epidermal differentiation markers, caspase 14 and filaggrin [20] were assessed in subjects with skin photodamage in a placebo controlled clinical trial [5]. Fig. 1A shows an example of biopsy samples stained at baseline and after 12 weeks of topical application of a formulation containing 5% MN and Fig. 1B shows quantification of caspase 14 and filaggrin in subjects treated with placebo or MN formulations. The presence of MN results in an increase relative to placebo of approximately 30% for caspase 14 and 20% for filaggrin. The placebo formulation substituted myristyl myristate for MN, ruling out any effects of myristyl alcohol that is generated as nicotinic acid is liberated from the prodrug.

Bottom Line: Receptor transcripts are greatly over-expressed in squamous cell cancers.In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling.The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Arizona Cancer Center and Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.

ABSTRACT

Background: Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein-coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells.

Results: Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.

Conclusions: The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis.

Show MeSH
Related in: MedlinePlus