To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to androgen independence and the process of metastatic spread of tumour. The complexity of the latter condition is likely to mitigate against the immediate development of relevant therapeutic approaches. However, the basis of androgen independence appears to be a problem of simpler dimensions and more amenable to treatment with current therapeutic technology. Since early tumour progression can be detected by an incomplete prostate-specific antigen (PSA) response to androgen withdrawal therapy, a study of the molecular biology of PSA gene regulation may well provide insight into new methods for preventing or delaying this problem. Mounting evidence suggests that ligand-independent activation of the androgen receptor may be one underlying mechanism of androgen independence. In the absence of androgen, a compensatory increase in the activity of cAMP-dependent protein kinase (PKA) enhances the ability of the androgen receptor to bind to the response elements regulating PSA gene expression. The activation of the androgen receptor through up-regulation of the PKA signal transduction pathway involves the amino-terminus of the androgen receptor, the function of which may be altered either by modifications such as phosphorylation, or through interactions with co-regulators or other proteins. Of therapeutic interest is the fact that this effect can be counteracted experimentally by the anti-androgen, bicalutamide, and clinically by several other similar agents. We speculate that the inhibition of PKA-activated androgen receptor might also be accomplished by decoy molecules that can bind to the relevant activated site on the amino-terminus or competitively interact with proteins recruited by the PKA pathway that are responsible for activating the receptor in the absence of androgen. Such molecules might include small mimetic substances or agents that can gain access to the nucleus of the cell.

This article has been cited by other articles:

				J. Chen, K. C. Ahn, N. A. Gee, M. I. Ahmed, A. J. Duleba, L. Zhao, S. J. Gee, B. D. Hammock, and B. L. Lasley Triclocarban Enhances Testosterone Action: A New Type of Endocrine Disruptor? Endocrinology, March 1, 2008; 149(3): 1173 - 1179. [Abstract] [Full Text] [PDF]

				J. Gong, J. Lee, H. Akio, P. N. Schlegel, and R. Shen Attenuation of Apoptosis by Chromogranin A-Induced Akt and Survivin Pathways in Prostate Cancer Cells Endocrinology, September 1, 2007; 148(9): 4489 - 4499. [Abstract] [Full Text] [PDF]

				S. N. Quayle, N. R. Mawji, J. Wang, and M. D. Sadar Androgen receptor decoy molecules block the growth of prostate cancer PNAS, January 23, 2007; 104(4): 1331 - 1336. [Abstract] [Full Text] [PDF]

				L. S. Lyons and K. L. Burnstein Vav3, a Rho GTPase Guanine Nucleotide Exchange Factor, Increases during Progression to Androgen Independence in Prostate Cancer Cells and Potentiates Androgen Receptor Transcriptional Activity Mol. Endocrinol., May 1, 2006; 20(5): 1061 - 1072. [Abstract] [Full Text] [PDF]

				T.-C. Yuan, S. Veeramani, F.-F. Lin, D. Kondrikou, S. Zelivianski, T. Igawa, D. Karan, S. K. Batra, and M.-F. Lin Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocr. Relat. Cancer, March 1, 2006; 13(1): 151 - 167. [Abstract] [Full Text] [PDF]

				M. S. Bhandari, J. Crook, and M. Hussain Should Intermittent Androgen Deprivation Be Used in Routine Clinical Practice? J. Clin. Oncol., November 10, 2005; 23(32): 8212 - 8218. [Abstract] [Full Text] [PDF]

				C. J.M. Best, J. W. Gillespie, Y. Yi, G. V.R. Chandramouli, M. A. Perlmutter, Y. Gathright, H. S. Erickson, L. Georgevich, M. A. Tangrea, P. H. Duray, et al. Molecular Alterations in Primary Prostate Cancer after Androgen Ablation Therapy Clin. Cancer Res., October 1, 2005; 11(19): 6823 - 6834. [Abstract] [Full Text] [PDF]

				L. Le, K. Chi, S. Tyldesley, S. Flibotte, D. L. Diamond, M. A. Kuzyk, and M. D. Sadar Identification of Serum Amyloid A as a Biomarker to Distinguish Prostate Cancer Patients with Bone Lesions Clin. Chem., April 1, 2005; 51(4): 695 - 707. [Abstract] [Full Text] [PDF]

				J Kim, L Jia, M R Stallcup, and G A Coetzee The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus J. Mol. Endocrinol., February 1, 2005; 34(1): 107 - 118. [Abstract] [Full Text] [PDF]

				R. J. Jin, Y. Wang, N. Masumori, K. Ishii, T. Tsukamoto, S. B. Shappell, S. W. Hayward, S. Kasper, and R. J. Matusik NE-10 Neuroendocrine Cancer Promotes the LNCaP Xenograft Growth in Castrated Mice Cancer Res., August 1, 2004; 64(15): 5489 - 5495. [Abstract] [Full Text] [PDF]

				Q. Wang, T. S. Udayakumar, T. S. Vasaitis, A. M. Brodie, and J. D. Fondell Mechanistic Relationship between Androgen Receptor Polyglutamine Tract Truncation and Androgen-dependent Transcriptional Hyperactivity in Prostate Cancer Cells J. Biol. Chem., April 23, 2004; 279(17): 17319 - 17328. [Abstract] [Full Text] [PDF]

				N. Blaszczyk, B. A. Masri, N. R. Mawji, T. Ueda, G. McAlinden, C. P. Duncan, N. Bruchovsky, H.-U. Schweikert, D. Schnabel, E. C. Jones, et al. Osteoblast-Derived Factors Induce Androgen-Independent Proliferation and Expression of Prostate-Specific Antigen in Human Prostate Cancer Cells Clin. Cancer Res., March 1, 2004; 10(5): 1860 - 1869. [Abstract] [Full Text] [PDF]

				C. W. Gregory, X. Fei, L. A. Ponguta, B. He, H. M. Bill, F. S. French, and E. M. Wilson Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer J. Biol. Chem., February 20, 2004; 279(8): 7119 - 7130. [Abstract] [Full Text] [PDF]

				J. L. Mohler, C. W. Gregory, O. H. Ford III, D. Kim, C. M. Weaver, P. Petrusz, E. M. Wilson, and F. S. French The Androgen Axis in Recurrent Prostate Cancer Clin. Cancer Res., January 15, 2004; 10(2): 440 - 448. [Abstract] [Full Text] [PDF]

				M. Fornaro, J. Plescia, S. Chheang, G. Tallini, Y.-M. Zhu, M. King, D. C. Altieri, and L. R. Languino Fibronectin Protects Prostate Cancer Cells from Tumor Necrosis Factor-{alpha}-induced Apoptosis via the AKT/Survivin Pathway J. Biol. Chem., December 12, 2003; 278(50): 50402 - 50411. [Abstract] [Full Text] [PDF]

				C. Wang, F. Yeung, P.-C. Liu, R. M. Attar, J. Geng, L. W. K. Chung, M. Gottardis, and C. Kao Identification of a Novel Transcription Factor, GAGATA-binding Protein, Involved in Androgen-mediated Expression of Prostate-specific Antigen J. Biol. Chem., August 22, 2003; 278(34): 32423 - 32430. [Abstract] [Full Text] [PDF]

				L. Jia, J. Kim, H. Shen, P. E. Clark, W. D. Tilley, and G. A. Coetzee Androgen Receptor Activity at the Prostate Specific Antigen Locus: Steroidal and Non-Steroidal Mechanisms Mol. Cancer Res., March 1, 2003; 1(5): 385 - 392. [Abstract] [Full Text] [PDF]

				B. F. Calvo, A. M. Levine, M. Marcos, Q. F. Collins, M. V. Iacocca, L. S. Caskey, C. W. Gregory, Y. Lin, Y. E. Whang, H. S. Earp, et al. Human Epidermal Receptor-2 Expression in Prostate Cancer Clin. Cancer Res., March 1, 2003; 9(3): 1087 - 1097. [Abstract] [Full Text] [PDF]

				Z. Weihua, R. Lathe, M. Warner, and J.-A. Gustafsson An endocrine pathway in the prostate, ERbeta , AR, 5alpha -androstane-3beta ,17beta -diol, and CYP7B1, regulates prostate growth PNAS, October 15, 2002; 99(21): 13589 - 13594. [Abstract] [Full Text] [PDF]

				L. Xia, D. Robinson, A.-H. Ma, H.-C. Chen, F. Wu, Y. Qiu, and H.-J. Kung Identification of Human Male Germ Cell-associated Kinase, a Kinase Transcriptionally Activated by Androgen in Prostate Cancer Cells J. Biol. Chem., September 13, 2002; 277(38): 35422 - 35433. [Abstract] [Full Text] [PDF]

				J. Dai, R. Shen, M. Sumitomo, R. Stahl, D. Navarro, M. C. Gershengorn, and D. M. Nanus Synergistic Activation of the Androgen Receptor by Bombesin and Low-Dose Androgen Clin. Cancer Res., July 1, 2002; 8(7): 2399 - 2405. [Abstract] [Full Text] [PDF]

				T. Ueda, N. Bruchovsky, and M. D. Sadar Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways J. Biol. Chem., February 22, 2002; 277(9): 7076 - 7085. [Abstract] [Full Text] [PDF]

				O. L. Zegarra-Moro, L. J. Schmidt, H. Huang, and D. J. Tindall Disruption of Androgen Receptor Function Inhibits Proliferation of Androgen-refractory Prostate Cancer Cells Cancer Res., February 1, 2002; 62(4): 1008 - 1013. [Abstract] [Full Text] [PDF]

				B. Cinar, K. S. Koeneman, M. Edlund, G. S. Prins, H. E. Zhau, and L. W. K. Chung Androgen Receptor Mediates the Reduced Tumor Growth, Enhanced Androgen Responsiveness, and Selected Target Gene Transactivation in a Human Prostate Cancer Cell Line Cancer Res., October 1, 2001; 61(19): 7310 - 7317. [Abstract] [Full Text] [PDF]

				M. E. Taplin and S.-M. Ho The Endocrinology of Prostate Cancer J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3467 - 3477. [Full Text] [PDF]

				X. Yu, P. Li, R. G. Roeder, and Z. Wang Inhibition of Androgen Receptor-Mediated Transcription by Amino-Terminal Enhancer of split Mol. Cell. Biol., July 15, 2001; 21(14): 4614 - 4625. [Abstract] [Full Text] [PDF]

				C. W. Gregory, B. He, R. T. Johnson, O. H. Ford, J. L. Mohler, F. S. French, and E. M. Wilson A Mechanism for Androgen Receptor-mediated Prostate Cancer Recurrence after Androgen Deprivation Therapy Cancer Res., June 1, 2001; 61(11): 4315 - 4319. [Abstract] [Full Text] [PDF]

				T. W.-M. Boileau, S. K. Clinton, S. Zaripheh, M. H. Monaco, S. M. Donovan, and J. W. Erdman Jr. Testosterone and Food Restriction Modulate Hepatic Lycopene Isomer Concentrations in Male F344 Rats J. Nutr., June 1, 2001; 131(6): 1746 - 1752. [Abstract] [Full Text]