The dark side of sunlight and melanoma
Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
Researchers uncover a previously unknown way UV light can act on melanin, spurring cancer-causing mutations hours after sun exposure.
Skin cancer is the most prevalent form of cancer, with a lifetime risk of 1 in 5 for Americans (1). Most skin cancers can be attributed to C→T and CC→TT mutations in DNA resulting from cyclobutane pyrimidine dimers (CPDs) produced by the direct absorption of UVB light (290 to 320 nm) present in sunlight (2). The most generally accepted mechanism for the formation of these mutations is that Cs or 5-methyl-Cs in the CPDs rapidly deaminate to Us or Ts, which are then replicated in an error-free manner. One might expect that photodamage would cease once out of the Sun, but Premi et al., on page 842 of this issue, show that this is not the case in melanocytes (3). A substantial fraction of UV damage to DNA in these cells may be occurring in the dark, by a novel pathway with important implications for melanoma formation.
Light and dark pathways (yellow and gray arrows, respectively) leading to melanoma-inducing mutations involving UV and biochemical-mediated formation of DNA photoproducts and oxidative damage
Comments by Peter Proctor, PhD, MD
This paper is particularly important because it relates to a putative common mechanism of causation and promotion of melanoma and other cancers by oxidative stress. E.g., over 50 years ago, Demopolous et al showed that inhibition of tyrosinase impedes growth and respiration of melanoma (http://jnci.oxfordjournals.org/content/35/5/823).
Similarly, many melanomas and other cancers have ectopic glutamic acid receptors ( mGLR’s ) essentially identical to some in the CNS. http://www.ncbi.nlm.nih.gov/pubmed/23171453 . These receptors materially-contribute to the cancer process. The anti-ALS drug Riluzole even has some activity in melanoma. The excitotoxic action of such receptors is well-known to be mediated by local generation of reactive oxygen species. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904214/ . Thus, e.g., Tempol is both anticancer and antiexcitotoxic, as are peroxinitrite scavengers such as uric acid, which is also antiexcitotoxic thru its more specific action on glutamate reuptake (http://stroke.ahajournals.org/content/39/8/e126.full ). More broadly, in some ways, ischemic injury and cancer are different sides of the same disease coin.
E.g., known Tempol targets include BRCA1, CtBP1, p53, PARP, HIF-1α, HIF-2α, VEGF, IL-6, BARD1, RAD51, uPAR, mGluRs, etc.. Several of these are involved in both cancer and in ischemic injury.
“Dark” photochemistry in melanins is an old concept (1-6). For a review and more cites, see Hill (1). E.g.,in the 1970’s, we postulated that melanin absorbs electronic energy from light (or whatever) and converts it to heat, rate-limited by a “phonon-bottleneck”. Too slow, melanin becomes “phototoxic”. We also cited Lamola re “dark” formation of pyrimidine dimers. noting the neurological symptoms of xeroderma pigmentosa as evidence that this happens in vivo.
Basically, the peculiar electronic properties of melanin are best explained by amorphous semiconductivity, likely augmented by proton-transport. Rediscovery of such conductive mechanisms for polyacetylenes (aka “melanins”) helped win the 2000 Nobel Prize in Chemistry. According to the Nobelists, the only place where such mechanisms do not hold is the special case of polyacetylene itself.
Also, genomic instability is not the only way in which “dark” photochemistry may promote cancer. Oxidative stress per se promotes cancer by so-called “redox-signaling”, involving redox-modulation of specific cell growth and check factors. Some of this originated with both us and researchers at the University of Iowa in the late 1970’s. Also see: www.redoxsignaling.com.
Tempol, the SOD-mimetic used in the study, itself shares this anticancer activity. In vitro, Tempol modulates numerous cancer-related factors such as BRCA1. Tempol is now in clinical trials for topical radioprotection, partially based upon one of our patents (“Topical Tempo”, US#5,352,442). A more recent patent (US#8,778,9695) claims its use for the treatment of fibrocystic disease of breast. Alas, despite the long-term connection to melanin research, to date, nobody seems to have tried Tempol against melanoma.
1.Hill HZ, The function of melanin or six blind people examine an elephant. Bioessays.1992 Jan;14(1):49-56.
2.McGinness, J. and Proctor, P. (1973). The importance of the fact that melanin is black. J. \theor. Bid. 39, 677-678.
3.Proctor, P., McGinness, J. and Corry, P. (1974). A hypothesis on the preferential destruction of melanized tissues. J.theor.Biology.48.19-22.
4.Proctor, P. (1976).The role of melanin in human neurological disorders.Pigment Cell 3,378-383.
5.McGinness.J.E., Kono.R. and Moorhead, W. D. (1979). The melanosome: Cytoprotective or Cytotoxic? Pigment Cell 4, 270-276.
6.Proctor,P.H. and McGinness,J.E.(1986).The function of melanin. Arch.Dermatol. 122, 507-508.