Androgen receptor remains critical for cell-cycle progression in androgen-independent CWR22 prostate cancer cells.
The majority of prostate cancers (PCa) that relapse after androgen deprivation therapy (androgen-independent PCa) continue to express androgen receptor (AR). To study the functional importance of AR in these tumors, we derived androgen-independent CWR22 PCa xenografts in castrated mice and generated a cell line from one of these xenografts (CWR22R3). Similarly to androgen-independent PCa in patients, the relapsed xenografts and cell line expressed AR and were resistant to treatment with bicalutamide. However, expression of the AR-regulated PSA gene in the CWR22R3 cell line was markedly decreased compared to the relapsed xenografts in vivo. Transfections with androgen-regulated reporter genes further indicated that the cells lacked androgen-independent AR transcriptional activity and were not hypersensitive to low androgen concentrations despite constitutive activation of the Erk/MAP kinases. Nonetheless, AR remained essential for androgen-independent growth because retroviral shRNA-mediated AR down-regulation resulted in marked long-term growth suppression. This was associated with increased levels of p27(kip1) and hypophosphorylation of retinoblastoma protein but not with decreases in D-type cyclin levels or MAP kinase activation. These results reveal a potentially critical function of AR in androgen-independent PCa that is distinct from its previously described transcriptional or nontranscriptional functions.
Yuan
Xin
X
Hematology/Oncology Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA. xyuan@bidmc.harvard
Li
Tong
T
Wang
Hongyun
H
Zhang
Tao
T
Barua
Moumita
M
Borgesi
Robert A
RA
Bubley
Glenn J
GJ
Lu
Michael L
ML
Balk
Steven P
SP
D000728:Androgens / Q000378:metabolism*; D000813:Anilides; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014105:Tosyl Compounds; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D000728:Androgens; D000813:Anilides; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D014157:Transcription Factors; C053541:bicalutamide; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D017430:Prostate-Specific Antigen