## 5 Studies and Mechanism about n-3 PUFAs and Melanoma
### In Vitro Studies  
One of the earliest pieces of evidence regarding n-3 PUFA in melanoma dates back to the beginning of the century, where [PERSON] et al. demonstrated that DHA was associated with decreased retinoblastoma protein (Rb) phosphorylation and cell cycle arrest (Figure 5). In this study, p27 has an inhibitory effect in the progression of the cell cycle which is mediated by CDK inhibition; therefore, the cells cannot progress from the G1 to S phase and apoptosis of melanoma cells occurs [142]. In most studies, in vitro models with various cell cultures are proposed. In the case of in vivo models, the n-3 fatty acid desaturase (Fat-1) transgenic mouse model is more commonly used, which can produce endogenous n-3 PUFA from n-6 PUFA in all tissues. In this section, we summarize the main studies regarding n-3 PUFA and melanoma, emphasizing some of the mechanisms proposed above. Regarding melanoma resistance to drugs such as cisplatin, [PERSON] et al. considered the use of new combinatorial strategies with n-3 PUFA, due to its antineoplastic properties, as an enhancing therapy for the treatment of this cancer [128]. This study demonstrated that DHA and EPA sensitize the cells to the cisplatin-induced inhibition of cell growth and migration by reverting cisplatin effects on DNA damage and protein excision repair cross-complementation group 1 (ERCC1) expression [128] (Figure 4). ERCC1, a crucial element in DNA repair vital for the repair of DNA adducts, has recently garnered significant attention in the context of this cancer. This is attributed to the fact that elevated expression of DNA repair genes plays a role in the heightened resistance exhibited by melanoma towards traditional DNA-damaging chemotherapeutic agents [143]. DHA and EPA also reverted the DUSP6 and pERK expressions, which regulate ERCC1 activation upward (Figure 5). In line with this, DUSP6 gene silencing prevented the effect of DHA, confirming that DHA acted on the DUSP6/p-ERK/ERCC1 repair pathways to sensitize melanoma cells to the anticancer effect of cisplatin [128] (Table 1). Inflammation stands as a crucial hallmark of cancer, capable of initiating and sustaining tumor development. The carcinogenic effects of COX-2 are supported by studies that show a growth-inhibitory effect in melanoma cells treated with COX-2 inhibitors [144,145]. Indeed, growing evidence supports the notion that the constant expression of COX-2 plays a pivotal role in the progression of malignant epithelial tumors, including melanoma. This is evident from the positive COX-2 status observed in oral and cutaneous melanomas, contrasting with the negative status found in all oral and cutaneous melanocytic nevi [146]. COX-2 expression in malignant melanoma is linked to the regulation of various factors, including tumor invasion, number of mitoses, tumor thickness, melanoma subtype, lymph node involvement and metastases [147]. Studies indicate that the overexpression of PGE2  
Figure 5: Molecular mechanisms of n-3 PUFAs in melanoma cells. Yellow circle with letter P means phosphorylation; \(\downarrow\), decrease; \(\uparrow\), increase; 5-FU, 5-fluorouracilacil; AA, arachidonic acid; AKT, protein kinase B; COX-2, cyclooxygenase-2; CXCR4, C-X-C chemokine receptor type 4; Cx43, connexin 43; DUSP6, dual specificity phosphatase 6; ERCC1, excision repair cross-complementation group 1 enzyme; ERK1/2, extracellular signal-regulated kinase 1/2; GLUT1, glucose transporter 1; MITF, melanocyte inducing transcription factor; n-3 PUFA, n-3 polyunsaturated fatty acids; PGE-2, prostaglandin E2; PGE-3, prostaglandin E3; PKC, protein kinase C; PTEN, phosphatase andensin homolog; Rack1, receptor for activated C kinase 1; Rb, retinoblastoma protein; TCF, T-cell factor; TGF-\(\beta\), transforming growth factor beta. is associated with skin cancer and correlates with a poor prognosis. On the other hand, PGE3 has been found to have anticancer effects (Figure 4). [PERSON] et al. and [PERSON] et al.