The Heat Shock Protein 90-Targeting Drug Cisplatin Selectively Inhibits Steroid Receptor Activation

Marcus C. Rosenhagen, Csaba Sõti, Ulrike Schmidt, Gabriela M. Wochnik, F. Ulrich Hartl, Florian Holsboer, Jason C. Young, Theo Rein
2003 Molecular Endocrinology  
Cisplatin is an antineoplastic drug that binds to DNA, thereby inhibiting cell division and tumor growth. Cisplatin may also disrupt the function of some proteins, including heat shock protein 90 (Hsp90). We report that cisplatin dose-dependently inhibited transcriptional activity of the androgen receptor and the glucocorticoid receptor (GR) in transient reporter assays. A truncated, hormoneindependent GR was only partially inhibited at significantly higher doses of cisplatin. Cisplatin
more » ... . Cisplatin treatment of neuroblastoma cells led to an immediate inhibition of hormone binding by GR, followed by proteasome-dependent degradation of the receptor. Other Hsp90-regulated proteins, i.e. the phosphokinases raf-1, lck, and c-src, were not affected, indicating a specific functional interference of cisplatin with the steroid receptors GR and androgen receptor. Cisplatin did not elicit a stress response, in contrast to geldanamycin. Immunoprecipitation revealed that cisplatin disrupts binding of GR to Hsp90. Moreover, cisplatin-treated Hsp90 was unable to associate with untreated ligand binding domain of GR. Reticulocyte lysate was able to restore hormone binding of GR in vitro, but not when the lysate was pretreated with geldanamycin. Our data reveal that cisplatin influences steroid receptors also independently of its DNA-mediated effects and, thus, suggest a novel modes of action for this cytostatic drug.
doi:10.1210/me.2003-0141 pmid:12869591 fatcat:dfkbgmsdzjeqldhg2kltjqi6oy