MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer

Abstract

Skin pigmentation is due to the accumulation of two types of melanin granules in the keratinocytes. Besides being the most potent blocker of ultraviolet radiation, the role of melanin in photoprotection is complex. This is because one type of melanin called eumelanin is UV absorbent, whereas the other, pheomelanin, is photounstable and may even promote carcinogenesis. Skin hyperpigmentation may be caused by stress or exposure to sunlight, which stimulates the release of α-melanocyte stimulating hormone (α-MSH) from damaged keratinocytes. Melanocortin 1 receptor (MC1R) is a key signaling molecule on melanocytes that responds to α-MSH by inducing expression of enzymes responsible for eumelanin synthesis. Persons with red hair have mutations in the MC1R causing its inactivation; this leads to a paucity of eumelanin production and makes red-heads more susceptible to skin cancer. Apart from its effects on melanin production, the α-MSH/MC1R signaling is also a potent anti-inflammatory pathway and has been shown to promote antimelanoma immunity. This review will focus on the role of MC1R in terms of its regulation of melanogenesis and influence on the immune system with respect to skin cancer susceptibility.

Figure 1. Building blocks of Pheomelanin (a) and Eumelanin (b)

Benzothiazine and Benzothiazol (a) are the building blocks of pheomelanin, they polymerize to form Pheomelanin. In case of eumelanin 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid shown in (b) polymerize to form eumelanin. The structures were drawn using ChemSketch.

Figure 2. Biosynthetic pathways involved in Eumelanin and Pheomelanin

TYR is involved in both eumelanin and pheomelanin synthesis, while TRP1, DCT (also called TRP2) are only involved in eumelanin (not pheomelanin) synthesis. Synthesis of eumelanin requires higher O2 consumption than pheomelanin. The structures were drawn using ChemSketch. MC1R, melanocortin 1 receptor; ASIP, agouti signaling protein; α-MSH, alpha-melanocyte stimulating hormone.

Figure 3. MC1R signaling and its downstream effectors

Keratinocyte mediators activate MITF which induces expression of enzymes for eumelanin production. Other factors secreted by keratinocytes can also induce MITF phosphorylation and induction of eumelanin synthesizing enzymes. ASP can act at different points of the pathway and inhibit α-MSH binding, can inhibit MITF phosphorylation and can also block cAMP synthesis and thus reduce eumelanin synthesis.

Figure 4. The immune system in light and dark colored individuals

In dark colored individuals after UVR, there is balanced inflammation, less ROS production, higher T-cells activity (higher IFN-γ responses) that can remove mutated cells. Further, high MC1R signaling in endothelial cells down regulates E-selectin, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) and less infiltration of macrophages and neutrophils. Proinflammatory and protumorigenic cytokine levels are lower. All this leads to microenvironment favorable to antitumor immunity. The light skinned individuals have high inflammatory response, high ROS generation and reduced cysteine stores which leads to T-cell inhibition. Together with high neutrophil and macrophages infiltration leads to an environment that is conducive for mutated cells to propagate and lead to tumor development.

Figure 5. Phylogenetic relationships and % identity of MC1Rs from various organisms

(a) Phylogenies were estimated using the MEGA 5 software. Numbers at the nodes indicate the percentage of replicate trees in which the associated species clustered together in the bootstrap test (1000 replicates). (b) Percent identity across various species is shown in the table. Red color indicates higher identity between species and blue indicates less identity. The sequences were Homo sapiens (Human, NP_002377); Pan troglodytes (Chimpanzee, JAA33119); Gorilla gorilla (Gorilla,AAX82901); Pongo pygmaeus (Orangutan, AAP30961); Papio anubis (Baboon, NP_001158061); Bos taurus (Cow, NP_776533); Balaenoptera physalus (Fin whale, ACR56643); Equus caballus (Horse, NP_001108006); Mus musculus (Mouse:C57BL/b, NP_032585); Sonora mutabilis (Mexican snake, AGA83481.1); Corvus corone (crow, ACA64022). The accession number from the rest of the mouse strains are Balb/c, (BAG85190); DBAF1, (CAA46589); C3H/HeJ, (ERS076383).

Figure 6. The MC1R receptor

The MC1R receptors and the alleles that are associated with red hair and light skinned (the RHC phenotype) (shown in red). RHC alleles (designated R) show odds ratios for red hair in the range of 50 to 120 (strong RHC alleles). These are the frequent R151C, R160W and D294H variants and the rare D84E and R142H alleles. The weaker RHC alleles (designated r) are V60L, V92M, R163Q, have odd ratios for red hair ranging roughly from 2 to 6 as discussed elsewhere (91). Cysteine residues are shown in blue. Most of these form important disulphide bonds.