Ciclosporin inhibits phorbol-ester-induced hyperplastic transformation and tumor promotion in mouse skin probably by suppression of Ca2+/calmodulin-dependent processes such as phosphorylation of elongation factor 2.
This study deals with the mechanism of the inhibitory effect exerted by the immunosuppressant ciclosporin (CsA) on phorbol-ester-induced inflammation, epidermal hyperplasia and tumor promotion in mouse skin in vivo. This effect coincides with an inhibition of the phosphorylation of a 100-kilodalton protein (p100) in epidermal cytosol in vitro, which has been identified as elongation factor 2 (EF-2) of protein biosynthesis. Phosphorylation of EF-2 is dependent on Ca2+ and calmodulin, and inhibition of EF-2 phosphorylation by CsA is due to an interaction of CsA with calmodulin. The EF-2 phosphorylation system has a metabolic half-life of 1.5 h probably due to a rather rapid turnover rate of the EF-2 kinase. Since CsA inhibits specifically 12-O-tetradecanoylphorbol-13-acetate (TAP)-stimulated but not basal protein synthesis in epidermis, it is proposed that Ca2+/calmodulin-dependent phosphorylation of EF-2 is involved in the induction of the hyperplastic response by TPA and that CsA suppresses TPA effects by inhibition of EF-2-phosphorylation and perhaps other calmodulin-dependent processes. The potential applicability of calmodulin inhibitors in the treatment of hyperproliferative skin diseases is discussed.
Gschwendt
M
M
German Cancer Research Center, Institute of Biochemistry, Heidelberg, FRG.
Kittstein
W
W
Marks
F
F
D000818:Animals; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D002848:Chromatography, DEAE-Cellulose; D003043:Cocarcinogenesis; D003513:Cycloheximide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D051379:Mice; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*
D002147:Calmodulin; D003524:Cyclosporins; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D010761:Phosphorus Radioisotopes; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium