This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yemelyanov, A. Articles by Budunova, I. Search for Related Content PubMed PubMed Citation Articles by Yemelyanov, A. Articles by Budunova, I.

Novel Steroid Receptor Phyto-Modulator Compound A Inhibits Growth and Survival of Prostate Cancer Cells

Departments of ¹ Dermatology and ² Obstetrics and Gynecology, Northwestern University, Chicago, Illinois and ³ Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado

Requests for reprints: Irina Budunova, Department of Dermatology, Northwestern University, Ward Building 9-332, 303 East Chicago Avenue, Chicago, IL 60611. Phone: 312-503-4679; Fax: 312-503-4325; E-mail: i-budunova{at}northwestern.edu.

Key Words: androgen receptor • glucocorticoid receptor • selective glucocorticoid receptor modulator • prostate cancer • apoptosis • growth

Androgen receptor (AR)– and glucocorticoid receptor (GR)– mediated signaling play opposite roles in prostate tumorigenesis: AR promotes prostate carcinoma (PC) development, whereas GR acts as a tumor suppressor. Compound A (CpdA) is a stable analogue of an aziridine precursor from the African shrub Salsola tuberculatiformis Botschantzev. It was shown recently that, in model cells, CpdA inhibits AR function and strongly enhances anti-inflammatory function of GR. We determined the effects of CpdA in prostate cells with different AR/GR status: (a) RWPE-1 cells (AR^low/GR^low), (b) PC3 and DU145 cells (GR⁺/AR^–), (c) LNCaP cells (GR^–/AR⁺), and (d) LNCaP-GR cells expressing both receptors. Similar to steroid hormones, CpdA induces nuclear translocation of both receptors in prostate cells. Despite this, CpdA inhibits DNA-binding and transactivation potential of AR. In addition, CpdA inhibits GR-mediated transactivation but induces GR transrepression via inhibition of several transcription factors, including nuclear factor-B, AP-1, Ets-1, Elk-1, SRF, CRE/ATF, and NFATc. CpdA strongly decreases growth and induces caspase-dependent apoptosis in highly malignant PC3 and DU145 cells and in other AR/GR-expressing PC cells. The cytostatic effect of CpdA is receptor dependent: down-regulation of GR or AR expression drastically attenuates CpdA-induced PC cell growth inhibition. Finally, virtual docking analysis indicates that CpdA shares binding cavities in AR and GR ligand-binding domains with corresponding hormones and forms hydrogen bonds (H-bond) with the same amino acids that are involved in H-bond formation during steroid binding. Overall, our data suggest that CpdA is a unique dual-target steroid receptor modulator that has a high potential for PC therapy. [Cancer Res 2008;68(12):4763–73]

This article has been cited by other articles:

				G. van Loo, M. Sze, N. Bougarne, J. Praet, C. Mc Guire, A. Ullrich, G. Haegeman, M. Prinz, R. Beyaert, and K. De Bosscher Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis Mol. Endocrinol., February 1, 2010; 24(2): 310 - 322. [Abstract] [Full Text] [PDF]

				A. M. Bode and Z. Dong Signal Transduction Molecules as Targets for Cancer Prevention Sci. Signal., February 24, 2009; 2(59): mr2 - mr2. [Abstract] [Full Text] [PDF]