Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Photoprotection by vitamin D compounds: uncovering markers that predict efficacy in reducing photocarcinogenesis. (#129)

Furkan A. Ince 1 , Julianne C. Nayar 1 , Artur Shariev 1 , Mark S. Rybchyn 2 , Manori De Silva 1 , Bianca Y. McCarthy 1 , Chen Yang 1 , Myriam Abboud 3 , Rebecca S. Mason 4 , Katie M. Dixon 1
  1. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  2. School of Chemical Engineering, University of New South Wales, Sydney, NSW, Australia
  3. College of Natural and Health Sciences, Zayed University, Dubai, ., United Arab Emirates
  4. School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia

The primary factors leading to development of ultraviolet radiation (UVR)-induced skin tumours are DNA damage and immunosuppression. The active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25D) reduces UVR-induced DNA damage, immunosuppression and skin tumours. Similar effects on DNA damage and immunosuppression were also observed using vitamin D-like compounds 1,25-dihydroxylumisterol and tetrahydrocurcumin, though reductions in skin tumours were not observed in a long term murine model. Therefore, it is important to uncover markers measurable in acute studies that can reliably identify agents that have potential to reduce UVR-induced skin tumours in a longer term model.

Phosphatase and tensin homolog (PTEN) and N-myc downstream regulated gene-1 (NDRG1) are suppressed in photocarcinogenesis. Following UVR exposure, we have shown that the levels of both markers are depleted in primary human melanocytes and Skh:hr1 mouse skin. Additionally, treatment with 1,25D immediately after UVR lead to increases in the levels of both proteins. Phosphorylation of cyclic AMP response element binding protein (CREB) was shown to increase in skin cells following UVR and is linked to carcinogenesis. Our preliminary data demonstrated a 1,25D-induced reduction in pCREB following UVR. The cytokine interleukin-6 (IL-6) is also increased following UVR. IL-10 was also observed to increase after UVR and is involved in immunosuppression. Both cytokines are reduced with 1,25D treatment.

Using the vitamin D-like compounds, we performed further studies in primary human skin cells, Skh:hr1 mice and ex vivo human skin. The aim of these studies was to develop a matrix to determine which markers could best predict the efficacy of the compounds to reduce UVR-induced skin tumours.

Testing for efficacy against UVR-induced skin tumours, while essential, is a long and expensive process.  If early markers were identified to reliably predict which agents were likely to reduce tumours, this could streamline selection of candidates for this testing.

  1. Dixon, K.M., et al., 1alpha,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation-Induced Skin Carcinogenesis. Cancer Prevention Research, 2011. 4(9): p. 1485-94
  2. Tongkao-On, W., Role of Vitamin D and Other Compounds in the Protection of Skin Cells from UV, in Physiology, School of Medical Sciences, University of Sydney, 2015 [PhD Thesis]
  3. Rybchyn, M.S., et al., Enhanced Repair of UV-Induced DNA Damage by 1,25-Dihydroxyvitamin D3 in Skin Is Linked to Pathways that Control Cellular Energy. J Invest Dermatol, 2018. 138(5): p. 1146-1156