Abstract
Taxol is a mitotoxin widely used to treat human cancers, including of the breast and ovary. However, taxol resistance (txr) limits treatment efficacy in human patients. To study chemoresistance in ovarian cancer, we established txr ovarian carcinoma cells derived from the SKOV3 cell lineage. The cells obtained were cross-resistant to other mitotoxins such as vincristine while they showed no resistance to the genotoxin cisplatin. Transcriptomic analysis identified 112 highly up-regulated genes in txr cells. Surprisingly, FK506-binding protein 5 (FKBP5) was transiently up-regulated 100-fold in txr cells but showed decreased expression in prolonged culture. Silencing of FKBP5 sensitized txr cells to taxol, whereas ectopic expression of FKBP5 increased resistance to the drug. Modulation of FKBP5 expression produced similar effects in response to vincristine but not to cisplatin. We observed that a panel of newly identified txr genes was trancriptionally regulated by FKBP5 and silencing of these genes sensitized cells to taxol. Notably, immunoprecipitation experiments revealed that FKBP5 forms a protein complex with the androgen receptor (AR), and this complex regulates the transcriptional activity of both proteins. Furthermore, we found 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 txr genes. Our findings suggest that mitotoxin-based treatment against ovarian cancer should be avoided when the Akt/FKBP5/AR axis is activated.
Highlights
The taxanes paclitaxel and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics, causing cell cycle arrest and apoptosis
Transcriptomic profiling revealed that FK506-binding protein 5 (FKBP5) mRNA was highly up-regulated in txr cells
These results indicate that the FKBP5 gene is inducible and its expression increases at the early stage of txr development, following taxol treatment
Summary
The taxanes paclitaxel (taxol) and docetaxel are microtubule-stabilizing agents that function primarily by interfering with spindle microtubule dynamics, causing cell cycle arrest and apoptosis. It is expected that at least 10 additional ABC proteins are involved in drug resistance [4] Structural advances in this field have provided a framework to decipher the kinetic and www.impactjournals.com/oncotarget molecular mechanisms by which ABC transporters couple ATP hydrolysis to substrate translocation [5]. Another group of membrane transporters involved in drug resistance is the SLC transporters, which function mainly as influx transporters [6]; these transporters are often downregulated in chemoresistant cells [7,8,9]. GSEA has been successfully used to identify metabolic pathways altered in many diseases, including to identify that activation of the PI3K/Akt pathway is associated with incomplete metabolic response in cervical cancer [12]
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