© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 21, 1869-1876,
November 3, 1999
© 1999 Oxford University Press
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Prostate Cancer Cell Cycle Regulators: Response to Androgen Withdrawal and Development of Androgen Independence
Affiliations of authors: D. B. Agus, W. Fox, D. W. Golde, H. I. Scher (Department of Medicine), C. Cordon-Cardo, M. Drobnjak (Department of Pathology), A. Koff (Sloan-Kettering Institute), Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: David B. Agus, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: d-agus{at}ski.mskcc.org).
BACKGROUND: Androgen withdrawal is a standard therapy for prostate cancer that results in a decrease in tumor volume and a decline in serum prostate-specific antigen in the majority of patients. To understand the factors associated with regression of prostate cancers after androgen withdrawal, we studied cell cycle regulator changes in the CWR22 human prostate cancer xenograft model. METHODS: Established tumors in nude athymic BALB/c mice were sampled at various times after androgen withdrawal and after the development of androgen independence. Changes in the expression of cell cycle regulators were categorized into early and mid-to-late events. RESULTS and CONCLUSIONS: Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis. The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1. These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.
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|
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|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
L. C. Amler, D. B. Agus, C. LeDuc, M. L. Sapinoso, W. D. Fox, S. Kern, D. Lee, V. Wang, M. Leysens, B. Higgins, et al. Dysregulated Expression of Androgen-responsive and Nonresponsive Genes in the Androgen-independent Prostate Cancer Xenograft Model CWR22-R Cancer Res., November 1, 2000; 60(21): 6134 - 6141. [Abstract] [Full Text]
|
|
|
|
|
|
L. M. Butler, D. B. Agus, H. I. Scher, B. Higgins, A. Rose, C. Cordon-Cardo, H. T. Thaler, R. A. Rifkind, P. A. Marks, and V. M. Richon Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Suppresses the Growth of Prostate Cancer Cells in Vitro and in Vivo Cancer Res., September 1, 2000; 60(18): 5165 - 5170. [Abstract] [Full Text]
|
|
|
|
|
|
S. McDonald, L. Brive, D. B. Agus, H. I. Scher, and K. R. Ely Ligand Responsiveness in Human Prostate Cancer: Structural Analysis of Mutant Androgen Receptors from LNCaP and CWR22 Tumors Cancer Res., May 1, 2000; 60(9): 2317 - 2322. [Abstract] [Full Text]
|
|
|
|
|
|
M. Drobnjak, I. Osman, H. I. Scher, M. Fazzari, and C. Cordon-Cardo Overexpression of Cyclin D1 Is Associated with Metastatic Prostate Cancer to Bone Clin. Cancer Res., May 1, 2000; 6(5): 1891 - 1895. [Abstract] [Full Text]
|
|
|
|
|
|
D. I. Quinn, S. M. Henshall, D. R. Head, D. Golovsky, J. D. Wilson, P. C. Brenner, J. J. Turner, W. Delprado, J. F. Finlayson, P. D. Stricker, et al. Prognostic Significance of p53 Nuclear Accumulation in Localized Prostate Cancer Treated with Radical Prostatectomy Cancer Res., March 1, 2000; 60(6): 1585 - 1594. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. R. Graff, B. W. Konicek, A. M. McNulty, Z. Wang, K. Houck, S. Allen, J. D. Paul, A. Hbaiu, R. G. Goode, G. E. Sandusky, et al. Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression J. Biol. Chem., August 4, 2000; 275(32): 24500 - 24505. [Abstract] [Full Text] [PDF]
|
|