fucoxanthin and Skin-Neoplasms

Every day, we come into contact with ultraviolet radiation (UVR). If under medical supervision, small amounts of UVR could be beneficial, the detrimental and hazardous effects of UVR exposure dictate an unbalance towards the risks on the risk-benefit ratio. Acute and chronic effects of ultraviolet-A and ultraviolet-B involve mainly the skin, the immune system, and the eyes. Photodamage is an umbrella term that includes general phototoxicity, photoaging, and cancer caused by UVR. All these phenomena are mediated by direct or indirect oxidative stress and inflammation and are strictly connected one to the other. Astaxanthin (ASX) and fucoxanthin (FX) are peculiar marine carotenoids characterized by outstanding antioxidant properties. In particular, ASX showed exceptional efficacy in counteracting all categories of photodamages, in vitro and in vivo, thanks to both antioxidant potential and activation of alternative pathways. Less evidence has been produced about FX, but it still represents an interesting promise to prevent the detrimental effect of UVR. Altogether, these results highlight the importance of digging into the marine ecosystem to look for new compounds that could be beneficial for human health and confirm that the marine environment is as much as full of active compounds as the terrestrial one, it just needs to be more explored.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Humans; Inflammation Mediators; Neoplasms, Radiation-Induced; Oxidative Stress; Skin; Skin Aging; Skin Neoplasms; Sunburn; Sunscreening Agents; Xanthophylls

Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.

Topics: Animals; Antioxidants; Cell Line; Cell Transformation, Neoplastic; Epigenesis, Genetic; Gene Expression Regulation; Gene Knockdown Techniques; Mice; NF-E2-Related Factor 2; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Skin Neoplasms; Tetradecanoylphorbol Acetate; Xanthophylls

Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA-induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention.

Topics: Animals; Antioxidant Response Elements; Cell Transformation, Neoplastic; CpG Islands; DNA Demethylation; Epidermal Cells; Epigenesis, Genetic; Gene Knockdown Techniques; Hep G2 Cells; Humans; Mice; NF-E2-Related Factor 2; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Tetradecanoylphorbol Acetate; Xanthophylls

The in vitro reactivity of capsanthin (1) and fucoxanthin (2) with peroxynitrite was investigated, and the reaction products produced by scavenging with peroxynitrite were analyzed. (14'Z)-Nitrocapsanthin (3) and 12-nitrocapsanthin (4) were isolated from the products of the reaction of capsanthin with peroxynitrite. Similarly, (14Z)-15-nitrofucoxanthin (5), (11Z)-11-nitrofucoxanthin (6), and (14Z,9'Z)-15-nitrofucoxanthin (7) were obtained from the reaction of peroxynitrite reaction with fucoxanthin. Capsanthin and fucoxanthin inhibited the nitration of tyrosine by peroxynitrite. Furthermore, nitrocapsanthins (3 and 4) and nitrofucoxanthins (5 and 6) exhibited an inhibitory effect on Epstein-Barr virus early antigen activation in Raji cells and an antiproliferative effect on human pancreatic carcinoma. Moreover, nitrocapsanthins (3 and 4) inhibited carcinogensis of mouse skin tumors initiated by 7,12-dimethylbenz[a]anthracene (DMBN).

Topics: Animals; Anticarcinogenic Agents; Burkitt Lymphoma; Cell Line, Tumor; Female; Free Radical Scavengers; Humans; Mice; Mice, Inbred ICR; Pancreatic Neoplasms; Papilloma; Peroxynitrous Acid; Skin Neoplasms; Tyrosine; Xanthophylls