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

Yira Bermudez, Claudia A. Benavente, Ralph G. Meyer, W. Russell Coyle, Myron K. Jacobson, Elaine L. Jacobson

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 Gi-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 Gi-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.

Original languageEnglish (US)
Article numbere20487
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - 2011

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Niacin
niacin
Skin Neoplasms
skin (animal)
Skin
receptors
keratinocytes
Cell membranes
Caspase 14
Keratinocytes
plasma membrane
dermal exposure
Cell Membrane
Pharmacology
adenylate cyclase
caspases
epidermis (animal)
Differentiation Antigens
Squamous Cell Neoplasms
squamous cell carcinoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nicotinic acid receptor abnormalities in human skin cancer : Implications for a role in epidermal differentiation. / Bermudez, Yira; Benavente, Claudia A.; Meyer, Ralph G.; Coyle, W. Russell; Jacobson, Myron K.; Jacobson, Elaine L.

In: PLoS One, Vol. 6, No. 5, e20487, 2011.

Research output: Contribution to journalArticle

Bermudez, Yira ; Benavente, Claudia A. ; Meyer, Ralph G. ; Coyle, W. Russell ; Jacobson, Myron K. ; Jacobson, Elaine L. / Nicotinic acid receptor abnormalities in human skin cancer : Implications for a role in epidermal differentiation. In: PLoS One. 2011 ; Vol. 6, No. 5.
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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 Gi-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 Gi-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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