Disruption of Androgen Receptor Function Inhibits Proliferation of Androgen-refractory Prostate Cancer Cells

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Disruption of Androgen Receptor Function Inhibits Proliferation of Androgen-refractory Prostate Cancer Cells¹

Ofelia L. Zegarra-Moro, Lucy J. Schmidt, Haojie Huang and Donald J. Tindall²

Departments of Biochemistry and Molecular Biology and Urology, Mayo Clinic, Rochester, Minnesota 55905

Prostate cancer cells depend on androgens and the androgen receptor(AR) for survival. However, after androgen ablation therapy,tumors relapse to an androgen-refractory state. To determinewhether the androgen receptor is critical for proliferationof androgen-refractory prostate cancer cells, we disrupted theactivity of the androgen receptor with an antibody and an ARmRNA hammerhead ribozyme in the following cell lines: LNCaP(androgen-sensitive), LNCaP-Rf and LNCaP-C4 (androgen-refractory),and DU-145 (androgen-insensitive). Microinjection of eitherantibody or ribozyme inhibited proliferation of androgen-refractorycells. These findings demonstrate that the AR is critical forproliferation of androgen-refractory cells, even in the absenceof androgens.

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L. Zhang, M. Johnson, K. H. Le, M. Sato, R. Ilagan, M. Iyer, S. S. Gambhir, L. Wu, and M. Carey
Interrogating Androgen Receptor Function in Recurrent Prostate Cancer
Cancer Res., August 1, 2003; 63(15): 4552 - 4560.
[Abstract] [Full Text] [PDF]

W. G. Nelson, A. M. De Marzo, and W. B. Isaacs
Prostate Cancer
N. Engl. J. Med., July 24, 2003; 349(4): 366 - 381.
[Full Text] [PDF]

I. V. Litvinov, A. M. De Marzo, and J. T. Isaacs
Is the Achilles' Heel for Prostate Cancer Therapy a Gain of Function in Androgen Receptor Signaling?
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 2972 - 2982.
[Full Text] [PDF]

R. E. Bakin, D. Gioeli, E. A. Bissonette, and M. J. Weber
Attenuation of Ras Signaling Restores Androgen Sensitivity to Hormone-refractory C4-2 Prostate Cancer Cells
Cancer Res., April 15, 2003; 63(8): 1975 - 1980.
[Abstract] [Full Text] [PDF]

R. E. Bakin, D. Gioeli, R. A. Sikes, E. A. Bissonette, and M. J. Weber
Constitutive Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway Promotes Androgen Hypersensitivity in LNCaP Prostate Cancer Cells
Cancer Res., April 15, 2003; 63(8): 1981 - 1989.
[Abstract] [Full Text] [PDF]

L. Neckers
Heat Shock Protein 90 Inhibition by 17-Allylamino-17- demethoxygeldanamycin: A Novel Therapeutic Approach for Treating Hormone-refractory Prostate Cancer : Commentary re: D. B. Solit et al., 17-Allylamino-17-demethoxygeldanamycin Induces the Degradation of Androgen Receptor and Her-2/neu and Inhibits the Growth of Prostate Cancer Xenografts. Clin. Cancer Res., 8: 986-993, 2002.
Clin. Cancer Res., May 1, 2002; 8(5): 962 - 966.
[Full Text] [PDF]

Y. B. Wetherill, C. E. Petre, K. R. Monk, A. Puga, and K. E. Knudsen
The Xenoestrogen Bisphenol A Induces Inappropriate Androgen Receptor Activation and Mitogenesis in Prostatic Adenocarcinoma Cells
Mol. Cancer Ther., May 1, 2002; 1(7): 515 - 524.
[Abstract] [Full Text] [PDF]