Linking the immunophilin FKBP5 to taxol resistance in ovarian cancer

Abstract

Taxol is a chemotherapeutic drug used to treat a number of cancers, including ovarian and breast cancers. However, taxol resistance limits treatment efficacy in cancer patients. To study the molecular mechanism of chemoresistance in ovarian cancer, we established taxol-resistant cells derived from the SKOV3 ovarian carcinoma cell lineage. Transcriptomic analysis identified 112 highly up-regulated genes in taxol-resistant cells. Among them, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100 fold in taxol-resistant cells but showed reduced expression following prolonged culture. FKBP5 silencing sensitized taxol-resistant cells to taxol, while overexpression of FKBP5 increased resistance to the drug. We observed that several of the newly identified taxol resistance genes were trancriptionally regulated by FKBP5, and silencing of these genes sensitized cells to taxol. Our experiments also revealed that FKBP5 forms a protein complex with the androgen receptor (AR), and this complex regulates the transcriptional activity of both proteins. In addition, we observed that the Akt kinase pathway is regulated by FKBP5. These results indicate that the FKBP5/AR complex may affect cancer cell sensitivity to taxol by regulating expression of taxol resistance genes. Our results suggest that taxol should not be used against ovarian cancer when the Akt/FKBP5/AR axis is activated.