Role of urocanic acid as an endogenous photoprotectant and as a therapeutic target for treating UV-induced melanoma and non-melanoma malignancies
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Overexposure to UV (ultraviolet) radiation has been linked to a number of deleterious effects on human health, particularly epidermal malignancies, which consist of both melanoma and non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. In the 1950’s, an epidermal compound known as Urocanic Acid (UCA) was discovered whose trans isoform was shown to display photoprotective effects against UV radiation. Not long after, the cis-UCA isomer was found to act as a mediator of immune suppression, causing UCA to be removed from all cosmetic products on the commercial market, most notably sunscreen. Numerous studies conducted after this finding further corroborated cis-UCA’s immunosuppressive properties, showing evidence for the ability of cis-UCA to inhibit contact hypersensitivity responses, delayed-type hypersensitivity responses, and allograft rejection. Early evidence for a mechanism of action behind cis-UCA’s immunosuppressive properties were widespread, including modulation of antigen-presenting cells, interaction with histamine receptors, and regulation of cytokine expression. The immunosuppressive nature of cis-UCA quickly became associated with an ability to facilitate cancerous progression, particularly regarding epidermal malignancies. Interesting theories were raised about the evolutionary basis for cis-UCA’s immunosuppressive nature, including speculation that cis-UCA was meant to induce immunosuppression following ultraviolet exposure in order to prevent autoimmune responses against sunburned epidermal cells. After the turn of the 20th century, new research continued to facilitate modern day understanding of the role of UCA. Evidence showed that UCA was ultimately derived from filaggrin within the stratum corneum, interacted with key immune effectors including T-lymphocytes and Langerhans cells, and potentially contributed to acidification of the stratum corneum. Despite the negative reputation cis-UCA has received in regards to facilitating skin cancer evasion of the immune system, research has shown that its immunosuppressive effects may allow it to serve as potent anti-inflammatory therapeutic. In regards to skin cancer, targeting of UCA as a therapeutic varies widely. Some have suggested using UCA as a measure of sunscreen efficacy, as an indirect target that when inhibited can reduce tumor growth, and as a biomarker for skin cancer risk. Others have begun developing UCA-based mimics that retain the benefits of UCA, while avoiding any deleterious effects. The role of UCA in non-melanoma and melanoma malignancies is not well understood, making targeting of UCA as a therapeutic challenging. The aim of this paper is to comprehensively review the scientific literature regarding the pre-21st century history of UCA, followed by an in-depth analysis of post-21st century research. The objective is to determine the overall potential of UCA to serve as a therapeutic target for UV-associated health conditions, most notably dermatologic malignancies.