Abstract
Melanoma is the deadliest type of skin cancer. Human melanomas often show hyperactivity of nitric oxide synthase (NOS) and NADPH oxidase (NOX), which, respectively, generate nitric oxide (NO·) and superoxide (O2·−). The NO· and O2 − react instantly with each other to generate peroxynitrite (ONOO−) which is the driver of melanin chemiexcitation. Melanoma precursors, the melanocytes, are specialized skin cells that synthesize melanin, a potent shield against sunlight's ultraviolet (UV) radiation. However, melanin chemiexcitation paradoxically demonstrates the melanomagenic properties of melanin. In a loop, the NOS activity regulates melanin synthesis, and melanin is utilized by the chemiexcitation pathway to generate carcinogenic melanin-carbonyls in an excited triplet state. These carbonyl compounds induce UV-specific DNA damage without UV. Additionally, the carbonyl compounds are highly reactive and can make melanomagenic adducts with proteins, DNA and other biomolecules. Here we review the role of the melanin chemiexcitation pathway in melanoma initiation, progression, and drug resistance. We conclude by hypothesizing a non-classical, positive loop in melanoma where melanin chemiexcitation generates carcinogenic reactive carbonyl species (RCS) and DNA damage in normal melanocytes. In parallel, NOS and NOX regulate melanin synthesis generating raw material for chemiexcitation, and the resulting RCS and reactive nitrogen species (RNS) regulate cellular proteome and transcriptome in favor of melanoma progression, metastasis, and resistance against targeted therapies.
Highlights
Skin is the largest human organ directly in contact with sunlight’s UV rays, a potent carcinogen
80% of the mutations in sunlight-induced melanoma are UV signature and cytosine to thymine transitions generated from cytosine-containing cyclobutane pyrimidine dimers (CPDs) [1,2,3]
We discovered an additional stress from endogenous activity of nitric oxide synthase (NOS) and NADPH oxidase (NOX) in pigmented melanocytes and not in the isogeneic albino
Summary
Chemiexcitation in Melanoma Progression and Drug Resistance. Melanoma is the deadliest type of skin cancer. The NOS activity regulates melanin synthesis, and melanin is utilized by the chemiexcitation pathway to generate carcinogenic melanin-carbonyls in an excited triplet state. These carbonyl compounds induce UV-specific DNA damage without UV. We conclude by hypothesizing a non-classical, positive loop in melanoma where melanin chemiexcitation generates carcinogenic reactive carbonyl species (RCS) and DNA damage in normal melanocytes. NOS and NOX regulate melanin synthesis generating raw material for chemiexcitation, and the resulting RCS and reactive nitrogen species (RNS) regulate cellular proteome and transcriptome in favor of melanoma progression, metastasis, and resistance against targeted therapies
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