Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity.
Androgen receptor (AR) transactivation is known to enhance prostate cancer cell survival. However, the precise effectors by which the prosurvival effects of androgen and AR drive prostate cancer progression are poorly defined. Here, we identify a novel feed-forward loop involving cooperative interactions between ligand-activated AR and heat-shock protein 27 (Hsp27) phospho-activation that enhance AR stability, shuttling, and transcriptional activity, thereby increasing prostate cancer cell survival. Androgen-bound AR induces rapid Hsp27 phosphorylation on Ser(78) and Ser(82) residues in an AR- and p38 kinase-dependent manner. After this androgen-induced, non-nuclear phospho-activation, Hsp27 displaces Hsp90 from a complex with AR to chaperone AR into the nucleus and interact with its response elements to enhance its genomic activity. Inhibition of Hsp27 phosphorylation, or knockdown using the antisense drug OGX-427, shifted the association of AR with Hsp90 to MDM2, increased proteasome-mediated AR degradation, decreased AR transcriptional activity, and increased prostate cancer LNCaP cell apoptotic rates. OGX-427 treatment of mice bearing LNCaP xenografts transfected with an androgen-regulated, probasin-luciferase reporter construct resulted in decreased bioluminescence and serum PSA levels as pharmacodynamic readouts of AR activity, as well as AR, Hsp27, and Hsp90 protein levels in LNCaP tumor tissue. These data identify novel nongenomic mechanisms involving androgen, AR, and Hsp27 activation that cooperatively interact to regulate the genomic activity of AR and justify further investigation of Hsp27 knockdown as an AR disrupting therapeutic strategy in prostate cancer.
Zoubeidi
Amina
A
The Prostate Centre, Vancouver General Hospital, and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Zardan
Anousheh
A
Beraldi
Eliana
E
Fazli
Ladan
L
Sowery
Richard
R
Rennie
Paul
P
Nelson
Colleen
C
Gleave
Martin
M
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D020218:Response Elements; D014158:Transcription, Genetic; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; D048051:p38 Mitogen-Activated Protein Kinases; D017430:Prostate-Specific Antigen; D046988:Proteasome Endopeptidase Complex