How does pheomelanin synthesis contribute to melanomagenesis?: Two distinct mechanisms could explain the carcinogenicity of pheomelanin synthesis

Abstract

Recently, we reported that melanoma risk in redheads is linked not only to pale skin, but also to the synthesis of the pigment - called pheomelanin - that gives red hair its color. We demonstrated that pheomelanin synthesis is associated with increased oxidative stress in the skin, yet we have not uncovered the chemical pathway between the molecule pheomelanin and the DNA damage that drives melanoma formation. Here, we hypothesize two possible pathways. On one hand, pheomelanin might generate reactive oxygen species (ROS) that directly or indirectly cause oxidative DNA damage. On the other hand, pheomelanin synthesis might consume cellular antioxidant stores and make the cell nucleus more vulnerable to other endogenous ROS. Uncovering the mechanistic pathway between pheomelanin and oxidative DNA damage will be an important step in developing strategies to lower melanoma risk in redheads.

Keywords: melanoma; pheomelanin; pigmentation; reactive oxygen species.

Figure 1. Two distinct mechanisms could explain the increase in oxidative stress associated with pheomelanin production

On one hand, pheomelanin is known to promote the formation of reactive oxygen species, which could tax cellular antioxidant reserves. On the other hand, the use of cysteine in pheomelanin biosynthesis could deplete cysteine-based cellular antioxidants. These two hypothetical mechanisms are not mutually exclusive.

Figure 2. Eumelanin polymers are composed of DHI and DHICA units, while pheomelanin polymers are composed of benzothiazole and benzothiazine units

Chemical structures of (a) eumelanin monomer units and (b) pheomelanin monomer units are shown above. DHI is 5,6-dihydroxyindole. DHICA is 5,6-dihydroxyindole-2-carboxylic acid. Oligomers of these units constitute the biological pigments [25].