Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression
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Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression. / Thoms, Kai-Martin; Kuschal, Christiane; Oetjen, Elke; Mori, Toshio; Kobayashi, Nobuhiko; Laspe, Petra; Boeckmann, Lars; Schön, Michael P; Emmert, Steffen.
in: EXP DERMATOL, Jahrgang 20, Nr. 3, 03.2011, S. 232-6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression
AU - Thoms, Kai-Martin
AU - Kuschal, Christiane
AU - Oetjen, Elke
AU - Mori, Toshio
AU - Kobayashi, Nobuhiko
AU - Laspe, Petra
AU - Boeckmann, Lars
AU - Schön, Michael P
AU - Emmert, Steffen
N1 - © 2010 John Wiley & Sons A/S.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Calcineurin
KW - Cell Line, Transformed
KW - Cell Survival
KW - Cyclosporine
KW - DNA Repair
KW - Fibroblasts
KW - Humans
KW - Immunosuppression
KW - Immunosuppressive Agents
KW - Lymphocytes
KW - Neoplasms
KW - Phosphorylation
KW - Pyrimidine Dimers
KW - RNA, Small Interfering
KW - Ribosomal Protein S6 Kinases, 70-kDa
KW - Sirolimus
KW - Transfection
KW - Ultraviolet Rays
U2 - 10.1111/j.1600-0625.2010.01213.x
DO - 10.1111/j.1600-0625.2010.01213.x
M3 - SCORING: Journal article
C2 - 21323745
VL - 20
SP - 232
EP - 236
JO - EXP DERMATOL
JF - EXP DERMATOL
SN - 0906-6705
IS - 3
ER -