Abstract
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.
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References
Ahonen TJ, Xie J, LeBaron MJ, Zhu J, Nurmi M, Alanen K et al. (2003). Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells. J Biol Chem 278: 27287–27292.
Amler LC, Agus DB, LeDuc C, Sapinoso ML, Fox WD, Kern S et al. (2000). Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res 60: 6134–6141.
Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V et al. (2005). Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood 106: 1400–1406.
Balk SP . (2002). Androgen receptor as a target in androgen-independent prostate cancer. Urology 60: 132–138; discussion 138-9.
Banerjee A, Periyasamy S, Wolf IM, Hinds Jr TD, Yong W et al. (2008). Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins. Biochemistry 47: 10471–10480.
Batch JA, Williams DM, Davies HR, Brown BD, Evans BA, Hughes IA et al. (1992). Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome. Hum Mol Genet 1: 497–503.
Chang CS, Kokontis J, Liao ST . (1988). Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240: 324–326.
Chen CD, Sawyers CL . (2002). NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Mol Cell Biol 22: 2862–2870.
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. (2004). Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33–39.
Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF . (2005). Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol 19: 1654–1666.
Cheung-Flynn J, Roberts PJ, Riggs DL, Smith DF . (2003). C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and FKBP52 cause differential binding to Hsp90. J Biol Chem 278: 17388–17394.
Cinar B, Yeung F, Konaka H, Mayo MW, Freeman MR, Zhau HE et al. (2004). Identification of a negative regulatory cis-element in the enhancer core region of the prostate-specific antigen promoter: implications for intersection of androgen receptor and nuclear factor-kappaB signalling in prostate cancer cells. Biochem J 379: 421–431.
Craft N, Sawyers CL . (1998). Mechanistic concepts in androgen-dependence of prostate cancer. Cancer Metastasis Rev 17: 421–427.
Dehm SM, Regan KM, Schmidt LJ, Tindall DJ . (2007). Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion independent prostate cancer cells. Cancer Res 67: 10067–10077.
Dehm SM, Tindall DJ . (2006). Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells. J Biol Chem 281: 27882–27893.
Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG . (2000). Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 141: 4107–4113.
Febbo PG, Lowenberg M, Thorner AR, Brown M, Loda M, Golub TR . (2005). Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. J Urol 173: 1772–1777.
Feldman BJ, Feldman D . (2001). The development of androgen-independent prostate cancer. Nat Rev Cancer 1: 34–45.
Galat A . (2003). Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Curr Top Med Chem 3: 1315–1347.
Giraudier S, Chagraoui H, Komura E, Barnache S, Blanchet B, LeCouedic JP et al. (2002). Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors. Blood 100: 2932–2940.
Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS et al. (2001). A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61: 4315–4319.
Grossmann ME, Huang H, Tindall DJ . (2001). Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 93: 1687–1697.
Haag P, Bektic J, Bartsch G, Klocker H, Eder IE . (2005). Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells. J Steroid Biochem Mol Biol 96: 251–258.
Han G, Buchanan G, Ittmann M, Harris JM, Yu X, Demayo FJ et al. (2005). Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci USA 102: 1151–1156.
Harding MW, Galat A, Uehling DE, Schreiber SL . (1989). A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341: 758–760.
Heinlein CA, Chang C . (2004). Androgen receptor in prostate cancer. Endocr Rev 25: 276–308.
Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, Smith DF, Scammell JG . (2003). The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness. Endocrinology 144: 2380–2387.
Igawa T, Lin FF, Lee MS, Karan D, Batra SK, Lin MF . (2002). Establishment and characterization of androgen-independent human prostate cancer LNCaP cell model. Prostate 50: 222–235.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C et al. (2006). Cancer statistics, 2006. CA Cancer J Clin 56: 106–130.
Jiang W, Cazacu S, Xiang C, Zenklusen JC, Fine HA, Berens M et al. (2008). FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia 10: 235–243.
Komura E, Chagraoui H, Mansat de Mas V, Blanchet B, de Sepulveda P, Larbret F et al. (2003). Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression. Exp Hematol 31: 622–630.
Landis SH, Murray T, Bolden S, Wingo PA . (1999). Cancer statistics, 1999. CA Cancer J Clin 49: 8–31, 1.
Lavery DN, McEwan IJ . (2005). Structure and function of steroid receptor AF1 transactivation domains: induction of active conformations. Biochem J 391: 449–464.
Lee SO, Lou W, Nadiminty N, Lin X, Gao AC . (2005). Requirement for NF-(kappa)B in interleukin-4-induced androgen receptor activation in prostate cancer cells. Prostate 64: 160–167.
Li TH, Zhao H, Peng Y, Beliakoff J, Brooks JD, Sun Z . (2007). A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells. Nucleic Acids Res 35: 2767–2776.
Liao X, Tang S, Thrasher JB, Griebling TL, Li B . (2005). Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. Mol Cancer Ther 4: 505–515.
Magee JA, Chang LW, Stormo GD, Milbrandt J . (2006). Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Endocrinology 147: 590–598.
Makkonen H, Kauhanen M, Paakinaho V, Jaaskelainen T, Palvimo JJ . (2009a). Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res 37: 4135–4148.
Makkonen H, Kauhanen M, Paakinaho V, Jaaskelainen T, Palvimo JJ . (2009b). Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res 37: 4135–4148.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83: 835–839.
McEwan IJ . (2004). Molecular mechanisms of androgen receptor-mediated gene regulation: structure–function analysis of the AF-1 domain. Endocr Relat Cancer 11: 281–293.
Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, Bittner M et al. (2001). Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20: 6718–6723.
Nakao R, Haji M, Yanase T, Ogo A, Takayanagi R, Katsube T et al. (1992). A single amino acid substitution (Met786–Val) in the steroid-binding domain of human androgen receptor leads to complete androgen insensitivity syndrome. J Clin Endocrinol Metab 74: 1152–1157.
Periyasamy S, Warrier M, Tillekeratne MP, Shou W, Sanchez ER . (2007). The immunophilin ligands cyclosporin A and FK506 suppress prostate cancer cell growth by androgen receptor-dependent and -independent mechanisms. Endocrinology 148: 4716–4726.
Pratt WB, Galigniana MD, Harrell JM, DeFranco DB . (2004). Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement. Cell Signal 16: 857–872.
Ratajczak T, Ward BK, Minchin RF . (2003). Immunophilin chaperones in steroid receptor signalling. Curr Top Med Chem 3: 1348–1357.
Reid J, Murray I, Watt K, Betney R, McEwan IJ . (2002). The androgen receptor interacts with multiple regions of the large subunit of general transcription factor TFIIF. J Biol Chem 277: 41247–41253.
Reynolds PD, Ruan Y, Smith DF, Scammell JG . (1999). Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51. J Clin Endocrinol Metab 84: 663–669.
Riggs DL, Cox MB, Tardif HL, Hessling M, Buchner J, Smith DF . (2007). Noncatalytic role of the FKBP52 peptidyl-prolyl isomerase domain in the regulation of steroid hormone signaling. Mol Cell Biol 27: 8658–8669.
Riggs DL, Roberts PJ, Chirillo SC, Cheung-Flynn J, Prapapanich V, Ratajczak T et al. (2003). The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J 22: 1158–1167.
Romano MF, Avellino R, Petrella A, Bisogni R, Romano S, Venuta S . (2004). Rapamycin inhibits doxorubicin-induced NF-kappaB/Rel nuclear activity and enhances the apoptosis of melanoma cells. Eur J Cancer 40: 2829–2836.
Scherr D, Swindle PW, Scardino PT . (2003). National Comprehensive Cancer Network guidelines for the management of prostate cancer. Urology 61: 14–24.
Schreiber SL, Crabtree GR . (1992). The mechanism of action of cyclosporin A and FK506. Immunol Today 13: 136–142.
Simental JA, Sar M, Lane MV, French FS, Wilson EM . (1991). Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem 266: 510–518.
Thalmann GN, Sikes RA, Wu TT, Degeorges A, Chang SM, Ozen M et al. (2000). LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate 44: 91–103 Jul 1; 44(2).
Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM et al. (2007). Integrative molecular concept modeling of prostate cancer progression. Nat Genet 39: 41–51.
Tranguch S, Cheung-Flynn J, Daikoku T, Prapapanich V, Cox MB, Xie H et al. (2005). Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc Natl Acad Sci USA 102: 14326–14331.
Tsai MJ, O'Malley BW . (1994). Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63: 451–486.
Vanaja DK, Mitchell SH, Toft DO, Young CY . (2002). Effect of geldanamycin on androgen receptor function and stability. Cell Stress Chaperones 7: 55–64.
Velasco AM, Gillis KA, Li Y, Brown EL, Sadler TM, Achilleos M et al. (2004). Identification and validation of novel androgen-regulated genes in prostate cancer. Endocrinology 145: 3913–3924.
Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E . (1992a). Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation. Biochemistry 31: 2393–2399.
Veldscholte J, Berrevoets CA, Zegers ND, van der Kwast TH, Grootegoed JA, Mulder E . (1992b). Hormone-induced dissociation of the androgen receptor-heat-shock protein complex: use of a new monoclonal antibody to distinguish transformed from nontransformed receptors. Biochemistry 31: 7422–7430.
Wochnik GM, Ruegg J, Abel GA, Schmidt U, Holsboer F, Rein T . (2005). FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem 280: 4609–4616.
Yong W, Yang Z, Periyasamy S, Chen H, Yucel S, Li W et al. (2007). Essential role for Co-chaperone Fkbp52 but not Fkbp51 in androgen receptor-mediated signaling and physiology. J Biol Chem 282: 5026–5036.
Zhu W, Zhang JS, Young CY . (2001). Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis 22: 1399–1403.
Acknowledgements
We thank Drs Theo Rein (Max Planck Institute of Psychiatry) and Marianne Sadar (British Columbia Cancer Agency) for the generous gift of Flag-tagged FKBP51 and PSA-luciferase reporter plasmid, respectively. This study was supported in part by National Institutes of Health grants DK73402 to WS and DK70127 to ERS.
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Periyasamy, S., Hinds, T., Shemshedini, L. et al. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 29, 1691–1701 (2010). https://doi.org/10.1038/onc.2009.458
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DOI: https://doi.org/10.1038/onc.2009.458
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