Abstract
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is β-catenin. Interest in the role of β-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of β-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous β-catenin on AR activity using Axin and RNA interference. Axin, which promotes β-catenin degradation, inhibited AR transcriptional activity. However, this did not require the β-catenin-binding domain of Axin. Depletion of β-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous β-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.
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References
Bhat RV, Shanley J, Correll MP, Fieles WE, Keith RA, Scott CW and Lee CM . (2000). Proc. Natl. Acad. Sci. USA, 97, 11074–11079.
Cheshire DR and Isaacs WB . (2003). Endocr. Relat. Cancer, 10, 537–560.
Chesire DR and Isaacs WB . (2002). Oncogene, 21, 8453–8469.
Chesire DR, Ewing CM, Gage WR and Isaacs WB . (2002). Oncogene, 21, 2679–2694.
Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD and Holder JC . (2000). Chem. Biol., 7, 793–803.
Cronauer MV, Schulz WA, Burchardt T, Anastasiadis AG, de la Taille A, Ackermann R and Burchardt M . (2003). Int. J. Oncol., 23, 1095–1102.
Cross DA, Alessi DR, Cohen P, Andjelkovich M and Hemmings BA . (1995). Nature, 378, 785–789.
Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD and Reith AD . (2001). J. Neurochem., 77, 94–102.
Demarchi F, Bertoli C, Sandy P and Schneider C . (2003). J. Biol. Chem., 278, 39583–39590.
Doble BW and Woodgett JR . (2003). J. Cell Sci., 116, 1175–1186.
Frame S and Cohen P . (2001). Biochem. J., 359, 1–16.
Franca-Koh J, Yeo M, Fraser E, Young N and Dale TC . (2002). J. Biol. Chem., 277, 43844–43848.
Fraser E, Young N, Dajani R, Franca-Koh J, Ryves J, Williams RS, Yeo M, Webster MT, Richardson C, Smalley MJ, Pearl LH, Harwood A and Dale TC . (2002). J. Biol. Chem., 277, 2176–2185.
Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS and Hayward SD . (2003). Nat. Med., 9, 300–306.
Giannini AL, Vivanco M and Kypta RM . (2000). J. Biol. Chem., 275, 21883–21888.
Gregory CW, Johnson Jr RT, Mohler JL, French FS and Wilson EM . (2001). Cancer Res., 61, 2892–2898.
Grimes CA and Jope RS . (2001). Prog. Neurobiol., 65, 391–426.
Hinoi T, Yamamoto H, Kishida M, Takada S, Kishida S and Kikuchi A . (2000). J. Biol. Chem., 275, 34399–34406.
Hsu W, Shakya R and Costantini F . (2001). J. Cell. Biol., 155, 1055–1064.
Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S and Kikuchi A . (1998). EMBO J., 17, 1371–1384.
Kikuchi A . (2000). Biochem. Biophys. Res. Commun., 268, 243–248.
Kypta RM, Su H and Reichardt LF . (1996). J. Cell Biol., 134, 1519–1529.
Li L, Yuan H, Weaver CD, Mao J, Farr III GH, Sussman DJ, Jonkers J, Kimelman D and Wu D . (1999). EMBO J., 18, 4233–4240.
Liao X, Thrasher JB, Holzbeierlein J, Stanley S and Li B . (2004). Endocrinology, 145, 2941–2949.
Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY and Chang C . (2003). J. Biol. Chem., 278, 50902–50907.
Mulholland DJ, Cheng H, Reid K, Rennie PS and Nelson CC . (2002). J. Biol. Chem., 277, 17933–17943.
Orme MH, Giannini AL, Vivanco MD and Kypta RM . (2003). Mol. Cell Neurosci., 24, 673–686.
Pawlowski JE, Ertel JR, Allen MP, Xu M, Butler C, Wilson EM and Wierman ME . (2002). J. Biol. Chem., 277, 20702–20710.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R and Weissman IL . (2003). Nature, 423, 409–414.
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL and MacDougald OA . (2000). Science, 289, 950–953.
Salas TR, Kim J, Vakar-Lopez F, Sabichi AL, Troncoso P, Jenster G, Kikuchi A, Chen SY, Shemshedini L, Suraokar M, Logothetis CJ, DiGiovanni J, Lippman SM and Menter DG . (2004). J. Biol. Chem., 279, 19191–19200.
Salas TR, Reddy SA, Clifford JL, Davis RJ, Kikuchi A, Lippman SM and Menter DG . (2003). J. Biol. Chem., 278, 41338–41346.
Smalley MJ, Sara E, Paterson H, Naylor S, Cook D, Jayatilake H, Fryer LG, Hutchinson L, Fry MJ and Dale TC . (1999). EMBO J., 18, 2823–2835.
Sramkoski RM, Pretlow II TG, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D and Jacobberger JW . (1999). In vitro Cell Dev. Biol. Anim., 35, 403–409.
Stambolic V and Woodgett JR . (1994). Biochem. J., 303 (Part 3), 701–704.
Truica CI, Byers S and Gelmann EP . (2000). Cancer Res., 60, 4709–4713.
van de Wetering M, Oving I, Muncan V, Pon Fong MT, Brantjes H, van Leenen D, Holstege FC, Brummelkamp TR, Agami R and Clevers H . (2003). EMBO Rep., 4, 609–615.
Wang L, Lin HK, Hu YC, Xie S, Yang L and Chang C . (2004). J. Biol. Chem., 279, 32444–32452.
Woodgett JR . (2001). Sci. STKE, 2001, RE12.
Yamamoto H, Kishida S, Kishida M, Ikeda S, Takada S and Kikuchi A . (1999). J. Biol. Chem., 274, 10681–10684.
Yang F, Li X, Sharma M, Sasaki CY, Longo DL, Lim B and Sun Z . (2002). J. Biol. Chem., 277, 11336–11344.
Yost C, Farr III GH, Pierce SB, Ferkey DM, Chen MM and Kimelman D . (1998). Cell, 93, 1031–1041.
Acknowledgements
We thank Charlotte Bevan for pSG5 AR, Marc van de Wetering and Hans Clevers for pTER and pTERβi, Trevor Dale and Jonathan Franca-Koh for AX2, AX2P, FRAT constructs and GSK-3 constructs and Christopher Gregory for CWR-R1 cells. We are grateful to Maria Vivanco (Institute of Cancer Research, London) for comments on the manuscript. This work was supported by the Prostate Cancer Charity, UK.
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Mazor, M., Kawano, Y., Zhu, H. et al. Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth. Oncogene 23, 7882–7892 (2004). https://doi.org/10.1038/sj.onc.1208068
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DOI: https://doi.org/10.1038/sj.onc.1208068
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