The Role of Prostaglandin Pathway and EP Receptors in Skin Cancer Development

Skin cancer is the most prevalent malignancy worldwide, with nonmelanoma skin cancers (NMSC) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) constituting most cases. Melanoma, although less common, is the most aggressive form of skin cancer and is responsible for the majority of skin cancer-related deaths. Prostaglandins, particularly prostaglandin E2 (PGE2), play a central role in the pathogenesis of skin cancer by mediating inflammation, angiogenesis, immune suppression, and tumor progression through the cyclooxygenase (COX)-PGE2 pathway. PGE2 exerts its effects via E-prostanoid (EP) receptors (EP1-EP4), which activate distinct signaling pathways that promote cell proliferation, survival, and metastasis. In melanoma, the COX-2-E2 axis is implicated in tumor-mediated immunosuppression and tumor growth. Although COX-2 inhibitors like celecoxib have shown efficacy in reducing NMSC incidence, their long-term use is limited by adverse effects. EP receptor antagonists represent a promising therapeutic alternative, offering targeted inhibition of PGE2-driven tumorigenesis with potentially fewer side effects. Emerging therapies, including combination strategies with immune checkpoint inhibitors, highlight the potential of precision medicine approaches to optimize the treatment and prevention of skin cancers, including melanoma. Further research is essential to elucidate the mechanisms of PGE2 signaling and refine therapeutic interventions targeting the COX-PGE2-receptor axis.