Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression

: 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.