Novel steroid receptor phyto-modulator compound a inhibits growth and survival of prostate cancer cells.
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-kappaB, 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.
Department of Dermatology, Northwestern University, Chicago, Illinois, USA.
Alexander
A
Yemelyanov
Jennifer
J
Czwornog
Lajos
L
Gera
Sonali
S
Joshi
Robert T
RT
Chatterton
Irina
I
Budunova
D000085:Acetates / Q000138:chemical synthesis / Q000494:pharmacology*; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D024202:Electrophoretic Mobility Shift Assay; D005021:Ethylamines / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008156:Luciferases / Q000378:metabolism; D008297:Male; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011869:Radioligand Assay; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014439:Tyramine / Q000031:analogs & derivatives
C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; C410798:AR protein, human; D000085:Acetates; D000726:Androgen Antagonists; D000728:Androgens; D005021:Ethylamines; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D008156:Luciferases; D017430:Prostate-Specific Antigen; D014439:Tyramine