Discovery and mechanistic characterization of a novel selective nuclear androgen receptor exporter for the treatment of prostate cancer.
Despite the success of medical strategies to reduce androgen levels in the treatment of prostate cancer, this disease invariably relapses to a castrate-resistant state that is generally fatal. Although it had been thought that androgen-insensitive cancers no longer relied on the androgen receptor (AR) for growth and survival, it is now clear that this is not the case. Because relapses are known to occur by many mechanisms that keep the AR functionally active, strategies to block AR accumulation in the nucleus may be therapeutically useful. Here, we report the discovery of a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression. SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser(650) of the AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells. Lastly, SNARE-1 functions as a tissue-selective AR inhibitor, as it fails to phosphorylate p38 MAPK in U2OS bone cells that are stably transfected with AR. In summary, SNARE-1 inhibits AR function by a mechanism that is distinct from clinically available antiandrogens, such that it might inform novel methods to block AR function in androgen-independent prostate cancer.
Narayanan
Ramesh
R
Preclinical Research and Development, GTx, Inc., Memphis, Tennessee 38163, USA.
Yepuru
Muralimohan
M
Szafran
Adam T
AT
Szwarc
Maria
M
Bohl
Casey E
CE
Young
Natalie L
NL
Miller
Duane D
DD
Mancini
Michael A
MA
Dalton
James T
JT
D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; C547582:N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide; D011412:Propanolamines; D011944:Receptors, Androgen; D048051:p38 Mitogen-Activated Protein Kinases