Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer.
In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization.
Narizhneva
Natalia V
NV
Anti-Cancer Drug Discovery Department, Cleveland BioLabs, Inc, Buffalo, NY, USA.
Tararova
Natalia D
ND
Ryabokon
Petro
P
Shyshynova
Inna
I
Prokvolit
Anatoly
A
Komarov
Pavel G
PG
Purmal
Andrei A
AA
Gudkov
Andrei V
AV
Gurova
Katerina V
KV
D000728:Androgens / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002369:Castration; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006131:Growth Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D000728:Androgens; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D054852:Small Molecule Libraries