Prostaglandins and Skin Cancer: An Old Pathway With New Insights in Cutaneous Oncology

The prostaglandin pathway is a well-known molecular signaling cascade with significant implications in inflammatory pathophysiology, yet its role in cancer development remains poorly understood. In this issue of the Journal, St. Denis et al. present a comprehensive review on the role of prostaglandins and their receptors in the pathogenesis of various cutaneous malignancies. They highlight that prostaglandin E2 (PGE2) and the key enzymes responsible for its production are overexpressed in multiple skin cancers, including keratinocyte cancers (basal cell cancers or BCCs and squamous cell cancers or SCCs), melanoma, and even Kaposi's sarcoma. Although cancer cells themselves can produce elevated levels of prostaglandins, St. Denis et al. emphasize that, in vivo, various other cells within the tumor microenvironment—including immune cells, endothelial cells, and cancer-associated fibroblasts—also contribute to prostaglandin production. Ultimately, excessive PGE2 levels can promote tumor initiation, progression, and even metastasis [1]. The question arises, how can we tame this dysfunctional pathway? Interestingly, certain supplements (or a well-balanced diet) may help reduce the risk of skin cancer. St. Denis et al. remind us that several bioactive compounds or nutraceuticals—such as green tea, ginger, curcumin, and soy—have the potential to reduce prostaglandin production, thereby mitigating UV-induced damage and chronic inflammation, two key drivers of skin cancer initiation and progression. Notably, flavonoids like apigenin (found in many fruits and vegetables), spirulina (a dried biomass of cyanobacteria), and resveratrol (a naturally occurring non-flavonoid polyphenol in grapes) have demonstrated cyclooxygenase 1 and 2 (COX-1/COX-2) inhibitory properties as well [1]. Pharmacological intervention using enzyme inhibitors and receptor antagonists is another exciting and maybe more predictable strategy, with opportunities to target prostaglandin production and intracellular signaling at multiple levels. The development of drugs that modulate PGE2 receptor (EP receptor) signaling could pave the way for novel skin cancer treatments with a more favorable side effect profile compared to direct COX inhibition. The most widely studied EP receptor in cancer development is EP4. Engagement of the EP4 receptor results in intracellular signaling pathways that prevent cancer cell apoptosis while supporting the proliferation and migration of malignant cells. In addition, EP4 signaling also regulates the immune microenvironment in cancers. Activation of EP4 inhibits antitumoral NK cell function and augments the immunosuppressive capacity of myeloid-derived suppressor cells. Blocking EP4 can revert these protooncogenic functions and could potentially hinder cancer development [2]. EP1 is another interesting target with profound tumor-promoting properties. Even though it is expressed at high levels in various cancers, it has the lowest affinity for PGE2 when compared to the other three EP receptors. This suggests that overproduction and the relative abundance of PGE2 in the cancer microenvironment can initiate signaling through EP1 and lead to tumorigenesis [2]. Over the past two decades, we have witnessed an exciting new era of rapid molecular discoveries shaping our understanding of health and disease. As a result, dermatology now benefits from a growing arsenal of targeted therapies, including biologics and small-molecule inhibitors [3]. The recent push to repurpose existing drugs for novel indications is equally compelling—think gabapentin for itch [4] or spironolactone for hair loss [5]. Targeting the prostaglandin pathway to prevent or treat skin cancers holds promise for both new and repurposed therapies. While EP receptor antagonists are being developed and tested in clinical trials, the adjunctive use of “old-school” COX inhibitors in select clinical scenarios could offer more immediate benefits in preventing and managing various skin cancers. The author declares no conflicts of interest.