title: 1α,25(OH)₂-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis.
abstract: Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)₂D₃ and 1α,25(OH)₂-lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)₂D₃ and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25(OH)₂D₃ and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid.
authors: Discipline of Physiology, School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors: Katie M
authors: KM
authors: Dixon
authors: Anthony W
authors: AW
authors: Norman
authors: Vanessa B
authors: VB
authors: Sequeira
authors: Ritu
authors: R
authors: Mohan
authors: Mark S
authors: MS
authors: Rybchyn
authors: Vivienne E
authors: VE
authors: Reeve
authors: Gary M
authors: GM
authors: Halliday
authors: Rebecca S
authors: RS
authors: Mason
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000517:prevention & control*; D002460:Cell Line; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology* / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: D016588:Anticarcinogenic Agents; D007166:Immunosuppressive Agents; D018167:Receptors, Calcitriol; D016159:Tumor Suppressor Protein p53; C002744:3-nitrotyrosine; D014443:Tyrosine; D002117:Calcitriol