AUTHOR=Premi Sanjay 

TITLE=Role of Melanin Chemiexcitation in Melanoma Progression and Drug Resistance

JOURNAL=Frontiers in Oncology

VOLUME=Volume 10 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.01305

DOI=10.3389/fonc.2020.01305

ISSN=2234-943X

ABSTRACT=Melanoma is the deadliest type of skin cancer which arises from melanocytes. Human melanomas often show hyperactivity of Nitric Oxide Synthase (NOS) and NADPH Oxidase (NOX) which respectively generate nitric oxide (NO·) and superoxide (O2·ˉ). The NO· and O2·ˉ react instantly with each other to generate peroxynitrite (ONOOˉ) 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 melanomagenic properties of melanin.  In a loop, the NOS activity regulates melanin synthesis and the melanin is utilized by chemiexcitation pathway to generate carcinogenic melanin-carbonyls in excited triplet state. These carbonyls induce UV-specific DNA damage without UV. Additionally, the carbonyls are highly reactive and can make melanomagenic adducts with proteins, DNA and other biomolecules. Here we review the role of 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.