Role of androgen receptor in the progression of human prostate tumor cells to androgen independence and insensitivity.
BACKGROUND
Various studies have implicated the androgen receptor (AR) in the progression of androgen-dependent human prostate cancer cells to androgen-independent and androgen-insensitive phenotypes, but the exact role of AR in progression is unclear.


METHODS
To mimic the clinical situation and test the role of AR in progression, we cultured androgen-dependent LNCaP 104-S prostate tumor cells in the presence of the antiandrogen Casodex (bicalutamide) to derive resistant (CDXR) clones. In a second step, we cultured CDXR cells in the presence of the androgen R1881, which generated androgen- and Casodex-insensitive (IS) cells. These cells were then characterized with regard to AR function and the effect of ectopic AR expression or AR knockdown on androgen sensitivity.


RESULTS
CDXR cells showed increased AR expression and transcriptional activity. CDXR cell proliferation was unaffected by Casodex but was repressed by androgen in vitro and in vivo. IS cells, on the other hand, had greatly reduced AR expression and activity compared to CDXR cells. Knockdown of AR expression in CDXR cells produced cells that were insensitive to androgen. Conversely, re-expression of AR in IS cells regenerated cells that were repressed by androgen. Knockdown of AR expression in 104-S cells produced cells that remained stimulated by androgen, while overexpression of AR in 104-S cells generated an androgen-repressed phenotype but did not confer androgen-independent growth.


CONCLUSIONS
Increased AR expression determines whether prostate cancer cells are repressed by androgen, but is not required for androgen independence. These results may have implications for anti-AR therapy for prostate cancer.
Kokontis
John M
JM
Ben May Institute for Cancer Research and the Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Hsu
Stephen
S
Chuu
Chih-pin
CP
Dang
Mai
M
Fukuchi
Junichi
J
Hiipakka
Richard A
RA
Liao
Shutsung
S
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D018450:Disease Progression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009570:Nitriles; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000494:pharmacology; D014105:Tosyl Compounds
C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015741:Metribolone; D013739:Testosterone; C053541:bicalutamide; D017430:Prostate-Specific Antigen