title: Deregulation of XPC and CypA by cyclosporin A: an immunosuppression-independent mechanism of skin carcinogenesis.
abstract: Skin cancer is the most common malignancy in organ transplant recipients, causing serious morbidity and mortality. Preventing and treating skin cancer in these individuals has been extraordinarily challenging. Following organ transplantation, cyclosporin A (CsA) has been used as an effective immunosuppressive to prevent rejection. Therefore immunosuppression has been widely assumed to be the major cause for increased skin carcinogenesis. However, the mechanism of skin carcinogenesis in organ transplant recipients has not been understood to date; specifically, it remains unknown whether these cancers are immunosuppression dependent or independent. Here, using both immunocompromised nude mice which are defective in mature T lymphocytes as an in vivo model and human keratinocytes as an in vitro model, we showed that CsA impairs genomic integrity in the response of keratinocytes to ultra violet B (UVB). Following UVB radiation, CsA inhibited UVB-induced DNA damage repair by suppressing the transcription of the DNA repair factor xeroderma pigmentosum C (XPC). In addition, CsA compromised the UVB-induced checkpoint function by upregulating the molecular chaperone protein cyclophilin A (CypA). XPC mRNA levels were lower, whereas CypA mRNA and protein levels were higher in human skin cancers than in normal skin. CsA-induced phosphoinositide 3-kinase(PI3K)/AKT activation was required for both XPC suppression and CypA upregulation. Blocking UVB damage or inhibiting the PI3K/AKT pathway prevented CsA-sensitized skin tumorigenesis. Our findings identified deregulation of XPC and CypA as key targets of CsA, and UVB damage and PI3K/AKT activation as two principal drivers for CsA-sensitized skin tumorigenesis, further supporting an immunosuppression-independent mechanism of CsA action on skin tumorigenesis.
authors: Section of Dermatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Weinong
authors: W
authors: Han
authors: Keyoumars
authors: K
authors: Soltani
authors: Mei
authors: M
authors: Ming
authors: Yu-Ying
authors: YY
authors: He
mesh_terms: D000818:Animals; D021984:Cyclophilin A / Q000096:biosynthesis*; D016572:Cyclosporine / Q000633:toxicity*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D016377:Organ Transplantation / Q000009:adverse effects*; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; C501002:Xpc protein, mouse; D016572:Cyclosporine; D021984:Cyclophilin A