title: Transcriptomic profiling of taxol-resistant ovarian cancer cells identifies FKBP5 and the androgen receptor as critical markers of chemotherapeutic response.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China. Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan, 333, Taiwan, Republic of China.
authors.forename: Nian-Kang
authors.initials: NK
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
authors.forename: Shang-Lang
authors.initials: SL
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
authors.forename: Pu-Yuan
authors.initials: PY
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
authors.forename: Chuck C-K
authors.initials: CC
authors.lastname: Chao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D017239:Paclitaxel; D011944:Receptors, Androgen; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C410798:AR protein, human