Nicotinic acid receptors as potential skin cancer prevention targets

A150

Nicotinic acid, also known as niacin, has been shown in mouse models of ultraviolet B-induced skin cancer to have a protective effect against nonmelanoma skin cancer (NMSC) by inhibiting photocarcinogenesis and photoimmunosuppression. Recently, two orphan human G-protein-coupled receptors HM74 and HM74A have been identified as the receptors for nicotinic acid. Since nicotinic acid has been used for decades as a lipid-lowering drug, research studies have focused on delineating the signaling pathway in adipose tissues. Thus, to date little is known about the expression and function of the nicotinic acid receptors in the skin, during skin differentiation, and in UV-irradiated skin. In order to test the hypothesis that nicotinic acid receptors are molecular targets for the prevention of NMSC, this study aimed to develop novel and specific nicotinic acid receptor antibodies in order to determine the role of nicotinic acid receptors in the skin. Polyclonal anti-peptide antibodies raised in rabbits were developed and specificity of the antibodies was tested by overexpression of both receptors in HeLa cells via Western blot, immunohistochemistry, and qRT-PCR analyses. When endogenous mRNA and protein expression of the nicotinic acid receptors were examined in HaCaT (keratinocytes) and CF3 (diploid fibroblast) cell lines and skin tissue sections, HM74A mRNA expression was detected in HaCaT, CF3, and skin tissue sections. However, HM74A protein expression analyses by Western blot and immunohistochemistry, showed that the HaCaT cell line, but not CF3, had strong endogenous receptor expression. Concurrently, human studies have shown that nicotinic acid delivered topically as a prodrug, myristyl nicotinate, enhances skin differentiation and barrier function. Therefore, the study herein will address the role of the nicotinic acid receptors in skin differentiation markers and its potential to prevent nonmelanoma skin cancer by driving differentiation. (This research was funded in part by NIH grants CA078447, CA106677, CA023074, CA027502, ES06694, and by Niadyne Development, Inc.)