Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.
The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.
Genomic Medicine Program, Houston Methodist Research Institute, 66670 Bertner Avenue, R8-114, Houston, Texas, 77030, United States of America.
Ji Ho
JH
Suh
Genomic Medicine Program, Houston Methodist Research Institute, 66670 Bertner Avenue, R8-114, Houston, Texas, 77030, United States of America.
Arundhati
A
Chattopadhyay
Genomic Medicine Program, Houston Methodist Research Institute, 66670 Bertner Avenue, R8-114, Houston, Texas, 77030, United States of America.
Douglas H
DH
Sieglaff
Border Biomedical Research Center, Dept. of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, Texas, 79902, United States of America.
Cheryl
C
Storer Samaniego
Border Biomedical Research Center, Dept. of Biological Sciences, University of Texas at El Paso, 500 W. University Ave., El Paso, Texas, 79902, United States of America.
Marc B
MB
Cox
Genomic Medicine Program, Houston Methodist Research Institute, 66670 Bertner Avenue, R8-114, Houston, Texas, 77030, United States of America.
Paul
P
Webb
D000726:Androgen Antagonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D000726:Androgen Antagonists; D011944:Receptors, Androgen; D051176:beta Catenin; D013196:Dihydrotestosterone; D005485:Flutamide