Apoptosis represents an effective way to eliminate cancer cells. Unfortunately, advanced prostate tumors eventually progress to androgen-independent tumors, which are resistant to current therapeutic approaches that act by triggering apoptosis. Vitamin A and its natural and synthetic analogs (retinoids) induce apoptosis in prostate cancer cells in vitro and in animal models, mainly through induction of retinoic acid receptor-beta (RARbeta). Expression levels of RARbeta, however, are significantly reduced in hormone-independent prostate cancer cells. Recently, a new class of synthetic retinoids related to 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) (also called CD437) that effectively induces apoptosis of both hormone-dependent and -independent prostate cancer cells in a retinoid receptor-independent manner was identified and has drawn a lot of attention in the field. The apoptotic effect of AHPN requires expression of orphan receptor TR3 (also called nur77 or NGFI-B). Paradoxically, TR3 expression is also induced by androgen and other mitogenic agents in prostate cancer cells to confer their proliferation. The recent finding that TR3 migrates from the nucleus to mitochondria to trigger apoptosis in response to AHPN suggests that the opposing biological activities of TR3 are regulated by its subcellular localization. Thus, agents that induce translocalization of TR3 from the nucleus to mitochondria will have improved efficacy against prostate cancer. TR3, therefore, represents an unexplored molecule that may be an ideal target for developing new agents for prostate cancer therapy.

This article has been cited by other articles:

				H.-Z. Chen, B.-X. Zhao, W.-X. Zhao, L. Li, B. Zhang, and Q. Wu Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria Carcinogenesis, November 1, 2008; 29(11): 2078 - 2088. [Abstract] [Full Text] [PDF]

				R. Maglietta, A. Piepoli, D. Catalano, F. Licciulli, M. Carella, S. Liuni, G. Pesole, F. Perri, and N. Ancona Statistical assessment of functional categories of genes deregulated in pathological conditions by using microarray data Bioinformatics, August 15, 2007; 23(16): 2063 - 2072. [Abstract] [Full Text] [PDF]

				F. Jin, X. Liu, Z. Zhou, P. Yue, R. Lotan, F. R. Khuri, L. W.K. Chung, and S.-Y. Sun Activation of Nuclear Factor-{kappa}B Contributes to Induction of Death Receptors and Apoptosis by the Synthetic Retinoid CD437 in DU145 Human Prostate Cancer Cells Cancer Res., July 15, 2005; 65(14): 6354 - 6363. [Abstract] [Full Text] [PDF]

				K D S. A. Wansa and G. E O Muscat TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors J. Mol. Endocrinol., June 1, 2005; 34(3): 835 - 848. [Abstract] [Full Text] [PDF]

				D. Pasquali, P. Chieffi, W. J Deery, G. Nicoletti, A. Bellastella, and A. A Sinisi Differential effects of all-trans-retinoic acid (RA) on Erk1/2 phosphorylation and cAMP accumulation in normal and malignant human prostate epithelial cells: Erk1/2 inhibition restores RA-induced decrease of cell growth in malignant prostate cells Eur. J. Endocrinol., April 1, 2005; 152(4): 663 - 669. [Abstract] [Full Text] [PDF]

				C Jeronimo, R Henrique, J Oliveira, F Lobo, I Pais, M R Teixeira, and C Lopes Aberrant cellular retinol binding protein 1 (CRBP1) gene expression and promoter methylation in prostate cancer J. Clin. Pathol., August 1, 2004; 57(8): 872 - 876. [Abstract] [Full Text] [PDF]

				X. Zheng, R. L. Chang, X.-X. Cui, G. E. Avila, S. Lee, Y. P. Lu, Y. R. Lou, W. J. Shih, Y. Lin, K. Reuhl, et al. Inhibitory Effect of 12-O-Tetradecanoylphorbol-13-acetate Alone or in Combination with All-trans-Retinoic Acid on the Growth of LNCaP Prostate Tumors in Immunodeficient Mice Cancer Res., March 1, 2004; 64(5): 1811 - 1820. [Abstract] [Full Text] [PDF]

				S. K. Kolluri, N. Bruey-Sedano, X. Cao, B. Lin, F. Lin, Y.-H. Han, M. I. Dawson, and X.-k. Zhang Mitogenic Effect of Orphan Receptor TR3 and Its Regulation by MEKK1 in Lung Cancer Cells Mol. Cell. Biol., December 1, 2003; 23(23): 8651 - 8667. [Abstract] [Full Text] [PDF]

				S. Y. James, F. Lin, S. K. Kolluri, M. I. Dawson, and X.-k. Zhang Regulation of Retinoic Acid Receptor {beta} Expression by Peroxisome Proliferator-activated Receptor {gamma} Ligands in Cancer Cells Cancer Res., July 1, 2003; 63(13): 3531 - 3538. [Abstract] [Full Text] [PDF]

				K. D. S. A. Wansa, J. M. Harris, G. Yan, P. Ordentlich, and G. E. O. Muscat The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine J. Biol. Chem., June 27, 2003; 278(27): 24776 - 24790. [Abstract] [Full Text] [PDF]

				W. F. Holmes, D. R. Soprano, and K. J. Soprano Elucidation of Molecular Events Mediating Induction of Apoptosis by Synthetic Retinoids Using a CD437-resistant Ovarian Carcinoma Cell Line J. Biol. Chem., November 15, 2002; 277(47): 45408 - 45419. [Abstract] [Full Text] [PDF]