Increased Melanogenesis is a Risk Factor for Oxidative DNA Damage— Study on Cultured Melanocytes and Atypical Nevus Cells^†

Abstract

Melanin synthesis is an oxygen-dependent process that acts as a potential source of reactive oxygen species (ROS) inside pigment-forming cells. The synthesis of the lighter variant of melanin, pheomelanin, consumes cysteine and this may limit the capacity of the cellular antioxidative defense. We show that tyrosine-induced melanogenesis in cultured normal human melanocytes (NHM) is accompanied by increased production of ROS and decreased concentration of intracellular glutathione. Clinical atypical (dysplastic) nevi (DN) regularly contain more melanin than do normal melanocytes (MC). We also show that in these cultured DN cells three out of four exhibit elevated synthesis of pheomelanin and this is accompanied by their early senescence. By using various redox-sensitive molecular probes, we demonstrate that cultured DN cells produce significantly more ROS than do normal MC from the same donor. Our experiments employing single-cell gel electrophoresis (comet assay) usually reveal higher fragmentation of DNA in DN cells than in normal MC. Even if in some cases the normal alkaline comet assay shows no differences in DNA fragmentation between DN cells and normal MC, the use of the comet assay with formamidopyrimidine DNA glycosylase can disclose that the DNA of the cultured DN cells harbor more oxidative damage than the DNA of normal MC from the same person.

Melanocytes and Oxidative Stress

“…Persons with fair skin, a poor ability to tan and a freckled complexion double their risk for melanoma [74]. In those persons with fair skin and red hair, specific mutations at the MC1R gene are responsible for the switch from eumelanin to phaeomelanin, inducing increased oxidative stress and higher risk of melanoma [35,36]. In a similar manner, it was demonstrated that recessive yellow mice with loss-of-function MC1R were developing more invasive melanoma than their albino counterparts [75].…”

“…Although cysteinylDOPA was suggested to have a role in scavenging ROS [34], this is only an intermediary in the chemical reaction, and phaeomelanin would behave as a unique 'living' polymer and biocatalyst that may grow by simple exposure to monomer building blocks and then trigger autoxidative processes [33]. This increased risk of oxidative damage with increased phaeomelanin production could potentially put nevus cells, recognized precursors of melanoma, at risk of oxidative damage [35,36]. To date, there is no clear view about whether eumelanin has a pro-oxidant or antioxidant capacity and this issue remains controversial.…”

Antioxidant Defense and UV-Induced Melanogenesis: Implications for Melanoma Prevention

“…Hypermelanosis induced by UVR has been previously suggested to associate with melanomageneis, although the role of UVR in the development of melanoma is complicated since melanogenesis may depend on several factors such as skin type, genetic influence, the extent of sun exposure (e.g., intensity, timing and duration of UVR) and types of moles representing disturbed melanin synthesis (Parvel et al, 2004;Rass & Reichrath, 2008;Tran et al, 2008). Melanin has been well recognized for its photoprotective properties, although melanogenic intermediates can be phototoxic and UVR-dependent elevated melanogenesis could thus be biologically harmful, genotoxic and contributed to melanoma initiation, especially in lightly pigmented individuals (Brenner & Hearing, 2008;Smit et al, 2008;Takeuchi et al, 2004;Yamaguchi et al, 2006). The desire to have fair or tanned skin depends on different cultures.…”

“…The ROS/ RNS primarily generated by UVA radiation can cause direct deleterious chemical modifications to cellular components including lipids, proteins and, especially DNA, which can eventually initiate melanomagenesis (Cotter et al, 2007). A disturbance in the antioxidant network and an accumulation of oxidative products were also demonstrated in skin tissues of melanoma skin cancer and in melanocytes from atypical nevi (Sander et al, 2003;Smit et al, 2008). Moreover, the presence of high levels of RNS, in particular nitric oxide (NO), and nitrosative products in cutaneous melanoma has been observed to be correlated with poor prognosis of patients and contributed to melanoma invasiveness (Chin & Deen, 2010).…”

Psychological support of skin cancer patients

“…Melanocytes are highly sensitive to oxidative stress, so that they die rapidly under exogenous and inflammatory oxidative stress. 28,29 Environmental stressors such as UV radiation but also psychosocial stress generate oxidative stress and promote mutagenesis (Fig. 1).…”