title: Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression.
abstract: Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4-pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A-induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling-dependent impairment of NER.
authors.affiliation: Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Germany.
authors.forename: Kai-Martin
authors.initials: KM
authors.lastname: Thoms
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuschal
authors.forename: Elke
authors.initials: E
authors.lastname: Oetjen
authors.forename: Toshio
authors.initials: T
authors.lastname: Mori
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Petra
authors.initials: P
authors.lastname: Laspe
authors.forename: Lars
authors.initials: L
authors.lastname: Boeckmann
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
mesh_terms: D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D000068338:Everolimus; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009369:Neoplasms / Q000209:etiology*; D010766:Phosphorylation / Q000187:drug effects; D011740:Pyrimidine Dimers / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D007166:Immunosuppressive Agents; D011740:Pyrimidine Dimers; D034741:RNA, Small Interfering; C058406:pyrimidine-pyrimidone dimer; D016572:Cyclosporine; D000068338:Everolimus; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D019703:Calcineurin; D020123:Sirolimus