Journal of Andrology, Vol 13, Issue 6 457-464, Copyright © 1992 by The American Society of Andrology

REVIEW

Androgen regulation of programmed death of normal and malignant prostatic cells

J. T. Isaacs, P. I. Lundmo, R. Berges, P. Martikainen, N. Kyprianou and H. F. English
Johns Hopkins Oncology Center, Johns Hopkins Medical Institute, Baltimore, Maryland.

Androgen-dependent normal prostatic glandular cells and androgen-dependent prostatic cancer cells can be induced to undergo cell death after androgen ablation. This death does not require the cells to proliferate and occurs as an energy-dependent process collectively referred to as "programmed cell death" in which the cells actively commit "suicide." Associated with this programmed cell death pathway is the enhanced expression of a series of genes and the fragmentation of the genomic DNA into nucleosomal oligomers. This genomic DNA fragmentation is the irreversible commitment step in the death of the cell and results from activation of Ca2+/Mg(2+)-dependent endonuclease activity within the cell nucleus. This activation is due to sustained elevation of intracellular free Ca2+ (Cai) induced after androgen ablation. Metastatic prostatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent cancer cells. Thus, androgen ablation is rarely curative since it only induces the programmed death of the androgen-dependent cancer cells without activating this pathway in the androgen-independent cancer cells within the patient. Androgen-independent prostatic cancer cells do not activate this death process after androgen ablation, since this does not induce a sustained increase in Cai. A new approach to treat androgen-independent prostatic cancer cells has focused on the use of chemotherapeutic agents to induce a sustained increase in Cai. These studies demonstrate that if such a sustained elevation in Cai is maintained, even androgen-independent prostatic cancer cells undergo programmed cell death.

This article has been cited by other articles:

				K. S. R. Sastry, Y. Karpova, S. Prokopovich, A. J. Smith, B. Essau, A. Gersappe, J. P. Carson, M. J. Weber, T. C. Register, Y. Q. Chen, et al. Epinephrine Protects Cancer Cells from Apoptosis via Activation of cAMP-dependent Protein Kinase and BAD Phosphorylation J. Biol. Chem., May 11, 2007; 282(19): 14094 - 14100. [Abstract] [Full Text] [PDF]

				O. Y. Khan, G. Fu, A. Ismail, S. Srinivasan, X. Cao, Y. Tu, S. Lu, and Z. Nawaz Multifunction Steroid Receptor Coactivator, E6-Associated Protein, Is Involved in Development of the Prostate Gland Mol. Endocrinol., March 1, 2006; 20(3): 544 - 559. [Abstract] [Full Text] [PDF]

				R. P. McCarthy, S. Zhang, D. G. Bostwick, J. Qian, J. N. Eble, M. Wang, H. Lin, and L. Cheng Molecular Genetic Evidence for Different Clonal Origins of Epithelial and Stromal Components of Phyllodes Tumor of the Prostate Am. J. Pathol., October 1, 2004; 165(4): 1395 - 1400. [Abstract] [Full Text] [PDF]

				P. Rocchi, A. So, S. Kojima, M. Signaevsky, E. Beraldi, L. Fazli, A. Hurtado-coll, K. Yamanaka, and M. Gleave Heat Shock Protein 27 Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone-Refractory Prostate Cancer Cancer Res., September 15, 2004; 64(18): 6595 - 6602. [Abstract] [Full Text] [PDF]

				X. Mu and C. Chang TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells J. Biol. Chem., October 31, 2003; 278(44): 42840 - 42845. [Abstract] [Full Text] [PDF]

				M. E. Wright, M.-J. Tsai, and R. Aebersold Androgen Receptor Represses the Neuroendocrine Transdifferentiation Process in Prostate Cancer Cells Mol. Endocrinol., September 1, 2003; 17(9): 1726 - 1737. [Abstract] [Full Text] [PDF]

				D. J. Lamb, E. Puxeddu, N. Malik, D. L. Stenoien, R. Nigam, G. Y. Saleh, M. Mancini, N. L. Weigel, and M. Marcelli Molecular Analysis of the Androgen Receptor in Ten Prostate Cancer Specimens Obtained Before and After Androgen Ablation J Androl, March 1, 2003; 24(2): 215 - 225. [Abstract] [Full Text] [PDF]

				P. Harkonen, S. Torn, R. Kurkela, K. Porvari, A. Pulkka, A. Lindfors, V. Isomaa, and P. Vihko Sex Hormone Metabolism in Prostate Cancer Cells during Transition to an Androgen-Independent State J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 705 - 712. [Abstract] [Full Text] [PDF]

				A. J. James, I. U. Agoulnik, J. M. Harris, G. Buchanan, W. D. Tilley, M. Marcelli, D. J. Lamb, and N. L. Weigel A Novel Androgen Receptor Mutant, A748T, Exhibits Hormone Concentration-Dependent Defects in Nuclear Accumulation and Activity Despite Normal Hormone-Binding Affinity Mol. Endocrinol., December 1, 2002; 16(12): 2692 - 2705. [Abstract] [Full Text] [PDF]

				P. S. Nelson, N. Clegg, H. Arnold, C. Ferguson, M. Bonham, J. White, L. Hood, and B. Lin The program of androgen-responsive genes in neoplastic prostate epithelium PNAS, September 3, 2002; 99(18): 11890 - 11895. [Abstract] [Full Text] [PDF]

				J. Singh, L. Young, D. J. Handelsman, and Q. Dong Prostate Epithelial Expression of a Novel Androgen Target Gene J Androl, September 1, 2002; 23(5): 652 - 660. [Abstract] [Full Text] [PDF]

				M. Chakraborty, S. G. Qiu, K. M. Vasudevan, and V. M. Rangnekar Par-4 Drives Trafficking and Activation of Fas and FasL to Induce Prostate Cancer Cell Apoptosis and Tumor Regression Cancer Res., October 1, 2001; 61(19): 7255 - 7263. [Abstract] [Full Text] [PDF]

				D. Waltregny, I. Leav, S. Signoretti, P. Soung, D. Lin, F. Merk, J. Y. Adams, N. Bhattacharya, N. Cirenei, and M. Loda Androgen-Driven Prostate Epithelial Cell Proliferation and Differentiation in Vivo Involve the Regulation of p27 Mol. Endocrinol., May 1, 2001; 15(5): 765 - 782. [Abstract] [Full Text]

				S. Lu, G. Jenster, and D. E. Epner Androgen Induction of Cyclin-Dependent Kinase Inhibitor p21 Gene: Role of Androgen Receptor and Transcription Factor Sp1 Complex Mol. Endocrinol., May 1, 2000; 14(5): 753 - 760. [Abstract] [Full Text]

				R. Yu, S. Mandlekar, S. Ruben, J. Ni, and A-N. T. Kong Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Androgen-independent Prostate Cancer Cells Cancer Res., May 1, 2000; 60(9): 2384 - 2389. [Abstract] [Full Text]

				S. Banerjee, P. P. Banerjee, and T. R. Brown Castration-Induced Apoptotic Cell Death in the Brown Norway Rat Prostate Decreases as a Function of Age Endocrinology, February 1, 2000; 141(2): 821 - 832. [Abstract] [Full Text] [PDF]

				M. Marcelli, M. Ittmann, S. Mariani, R. Sutherland, R. Nigam, L. Murthy, Y. Zhao, D. DiConcini, E. Puxeddu, A. Esen, et al. Androgen Receptor Mutations in Prostate Cancer Cancer Res., February 1, 2000; 60(4): 944 - 949. [Abstract] [Full Text]

				S. Lu, S. Y. Tsai, and M.-J. Tsai Molecular Mechanisms of Androgen-Independent Growth of Human Prostate Cancer LNCaP-AI Cells Endocrinology, November 1, 1999; 140(11): 5054 - 5059. [Abstract] [Full Text]

				S. Lu, M. Liu, D. E. Epner, S. Y. Tsai, and M.-J. Tsai Androgen Regulation of the Cyclin-Dependent Kinase Inhibitor p21 Gene through an Androgen Response Element in the Proximal Promoter Mol. Endocrinol., March 1, 1999; 13(3): 376 - 384. [Abstract] [Full Text]

				K. A. Moffatt, W. U. Johannes, and G. J. Miller 1{{alpha}},25-Dihydroxyvitamin D3 and Platinum Drugs Act Synergistically to Inhibit the Growth of Prostate Cancer Cell Lines Clin. Cancer Res., March 1, 1999; 5(3): 695 - 703. [Abstract] [Full Text] [PDF]

				M. Marcelli, G. R. Cunningham, M. Walkup, Z. He, L. Sturgis, C. Kagan, R. Mannucci, I. Nicoletti, B. Teng, and L. Denner Signaling Pathway Activated during Apoptosis of the Prostate Cancer Cell Line LNCaP: Overexpression of Caspase-7 as a New Gene Therapy Strategy for Prostate Cancer Cancer Res., January 1, 1999; 59(2): 382 - 390. [Abstract] [Full Text] [PDF]

				J. Ghosh and C. E. Myers Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells PNAS, October 27, 1998; 95(22): 13182 - 13187. [Abstract] [Full Text] [PDF]