Slominski Radomir M, Sarna Tadeusz, Płonka Przemysław M, Raman Chander, Brożyna Anna A, Slominski Andrzej T
Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, United States.
Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Front Oncol. 2022 Mar 14;12:842496. doi: 10.3389/fonc.2022.842496. eCollection 2022.
Melanin pigment plays a critical role in the protection against the harmful effects of ultraviolet radiation and other environmental stressors. It is produced by the enzymatic transformation of L-tyrosine to dopaquinone and subsequent chemical and biochemical reactions resulting in the formation of various 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and 5,6-dihydroxyindole (DHI) oligomers-main constituents of eumelanin, and benzothiazine and benzothiazole units of pheomelanin. The biosynthesis of melanin is regulated by sun exposure and by many hormonal factors at the tissue, cellular, and subcellular levels. While the presence of melanin protects against the development of skin cancers including cutaneous melanoma, its presence may be necessary for the malignant transformation of melanocytes. This shows a complex role of melanogenesis in melanoma development defined by chemical properties of melanin and the nature of generating pathways such as eu- and pheomelanogenesis. While eumelanin is believed to provide radioprotection and photoprotection by acting as an efficient antioxidant and sunscreen, pheomelanin, being less photostable, can generate mutagenic environment after exposure to the short-wavelength UVR. Melanogenesis by itself and its highly reactive intermediates show cytotoxic, genotoxic, and mutagenic activities, and it can stimulate glycolysis and hypoxia-inducible factor 1-alpha (HIF-1α) activation, which, combined with their immunosuppressive effects, can lead to melanoma progression and resistance to immunotherapy. On the other hand, melanogenesis-related proteins can be a target for immunotherapy. Interestingly, clinicopathological analyses on advanced melanomas have shown a negative correlation between tumor pigmentation and diseases outcome as defined by overall survival and disease-free time. This indicates a "Yin and Yang" role for melanin and active melanogenesis in melanoma development, progression, and therapy. Furthermore, based on the clinical, experimental data and diverse effects of melanogenesis, we propose that inhibition of melanogenesis in advanced melanotic melanoma represents a realistic adjuvant strategy to enhance immuno-, radio-, and chemotherapy.
黑色素在抵御紫外线辐射和其他环境应激源的有害影响方面起着关键作用。它是由L-酪氨酸通过酶促转化为多巴醌，随后经过化学和生化反应生成的，这些反应导致形成各种5,6-二羟基吲哚-2-羧酸（DHICA）和5,6-二羟基吲哚（DHI）低聚物——真黑素的主要成分，以及褐黑素的苯并噻嗪和苯并噻唑单元。黑色素的生物合成在组织、细胞和亚细胞水平上受阳光照射和许多激素因素的调节。虽然黑色素的存在可预防包括皮肤黑色素瘤在内的皮肤癌的发生，但其存在对于黑素细胞的恶性转化可能是必要的。这表明黑色素生成在黑色素瘤发展中具有复杂的作用，这一作用由黑色素的化学性质以及真黑素和褐黑素生成途径的性质所定义。虽然真黑素被认为通过作为一种有效的抗氧化剂和防晒剂来提供辐射防护和光防护，但褐黑素的光稳定性较差，在暴露于短波长紫外线辐射后会产生诱变环境。黑色素生成本身及其高反应性中间体具有细胞毒性、遗传毒性和诱变活性，并且它可以刺激糖酵解和缺氧诱导因子1-α（HIF-1α）的激活，这些作用与其免疫抑制作用相结合，可导致黑色素瘤进展和对免疫治疗的抵抗。另一方面，与黑色素生成相关的蛋白质可以成为免疫治疗的靶点。有趣的是，对晚期黑色素瘤的临床病理分析表明，肿瘤色素沉着与由总生存期和无病时间所定义的疾病结局之间呈负相关。这表明黑色素和活跃的黑色素生成在黑色素瘤的发展、进展和治疗中具有“阴阳”作用。此外，基于临床、实验数据以及黑色素生成的多种效应，我们提出在晚期黑素性黑色素瘤中抑制黑色素生成是一种切实可行的辅助策略，可增强免疫治疗、放射治疗和化学治疗的效果。
