Inhibition of Photocarcinogenesis by Platelet-Activating Factor or Serotonin Receptor Antagonists

Abstract

The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UVinduced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT 2A ) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT 2A to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT 2A receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT 2A receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT 2A receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT 2A receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression.

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…73 This rapid production and release of PAF leads to suppression of adaptive immune responses 10 and contributes to the development of UV-induced skin cancer. 74 PAF mediates some of these biological effects by modulating the production of cytokines in target cells. For example, keratinocytes produce IL-10, 10 whereas fibroblasts secrete IL-6 and IL-8, 75 in response to PAF stimulation.…”

Crosstalk between Protease-activated Receptor 1 and Platelet-activating Factor Receptor Regulates Melanoma Cell Adhesion Molecule (MCAM/MUC18) Expression and Melanoma Metastasis

“…PAF is an essential inflammatory biolipid. It is a mediator of platelet activation and inflammation that has been suggested to promote tumor growth and angiogenesis of breast, prostate, non-melanoma, and melanoma skin cancers (41)(42)(43). Although the molecular mechanisms of PAFR action in cancer remain to be investigated, in various normal cell types, PAF induces the expression of inflammatory and angiogenic molecules such as IL-6, IL-8, IL-10, cyclooxygenase-2, vascular endothelial growth factor, inducible nitric-oxide synthase, and tumor necrosis factor-␣ 58 -61).…”

Pathobiology of actinic keratosis: Ultraviolet-dependent keratinocyte proliferation

“…50 Treatment of mice with PAF or 5-HT 2A receptor antagonists blocked skin cancer induction and its progression. 23 In addition to blocking immunosuppression, PAF or 5-HT 2A receptor antagonists modulate DNA repair, accelerating nucleotide excision repair and reducing the formation of 8-oxo-deoxyguanosine, as shown both in vivo and in vitro. 51 Given that both PAF and cis-UCA increase ROS, an action that can be blocked by their respective antagonists, ROS may link genetic damage, DNA repair, and immunosuppression driven by PAF and cis-UCA.…”