FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A.
Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa.
Periyasamy
S
S
Center for Diabetes and Endocrine Research (CeDER), Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614-2598, USA. sumudra.periyasamy@utoledo.edu
Hinds
T
T
Shemshedini
L
L
Shou
W
W
Sanchez
E R
ER
D000728:Androgens / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5; D000097322:Peptidyl-Prolyl Isomerase D
D000728:Androgens; D021983:Cyclophilins; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D015741:Metribolone; D011944:Receptors, Androgen; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D