Regulation of cyclic AMP as a prevention strategy for melanoma

CN15-02

Melanoma occurs mainly in fair-skinned individuals who burn rather than tan after ultraviolet (UV) exposure. This phenotype correlates with dysfunction in the melanocortin-1 receptor (Mc1r), the receptor on melanocytes for melanocyte stimulating hormone. When the activity of this Gs-protein coupled receptor is sub-optimal, there is muted cytoplasmic cAMP signaling and the melanocyte produces pheomelanin, a sulfated lighter pigment with poor UV-blocking ability, rather than eumelanin, the brown-black melanin polymer highly protective against UV injury. Our goal is to develop novel UV-protective strategies by pharmacologically rescuing eumelanin production in fair-skinned individuals who, because of Mc1r loss-of-function polymorphisms, cannot melanize effectively. Using a transgenic murine model of “humanized skin” of variant pigment composition, we show that UV damage in the skin (including carcinogenesis) is much greater in pheomelanotic animals than in eumelanotic animals. Furthermore, we find that topical application of forskolin, a direct activator of adenylyl cyclase, by-passes defective Mc1r signaling in pheomelanotic mice and rescues robust eumelanin production in the skin. Importantly, this pigment accumulation is highly protective against both acute and chronic UV injury. Pharmacologic eumelanization is well-tolerated by the animals over several months, and does not induce damage response signals in the skin in contrast to natural tanning responses after UV exposure. Forskolin-induced eumelanin persists as long as the drug is applied daily to the surface of the skin (now tested for four months) and is reversible upon discontinuation of topical treatments. Melanin deposition after forskolin application mimics the natural nuclear capping pattern found in UV-exposed skin of darker pigment phenotype, and induces thickening of the epidermis much like natural UV-induced tanning responses. Manipulating natural melanin pigments by small molecules (sunless tanning) holds great potential for being an important novel UV-protective strategy with particular benefit to those populations most at risk of melanoma and other skin cancers.