Hormonal regulation of beta2-adrenergic receptor level in prostate cancer.
BACKGROUND
Androgen deprivation is the only effective systemic therapy available for patients with prostatic carcinoma, but is associated with a gradual transition to a hormone-refractory prostate cancer (HRCAP) in which ligand-independent activation of the androgen receptor has been implicated. The beta(2)-adrenergic receptor (beta(2)-AR) is a well-known activator of the androgen receptor.


METHODS
Prostatic cell lines were analyzed using cDNA micro-array, real time RT-PCR, radioligand binding assay, cAMP measurements, transfection and thymidine incorporation assay. Clinical specimens were studied by immunohistochemistry and Affymetrix microarrays.


RESULTS
Here, we show that beta(2)-AR was transiently down-regulated both at mRNA- and protein levels when hormone-sensitive prostate cancer cells, LNCaP, were cultured in steroid stripped medium (charcoal-stripped fetal calf serum) or when the cells were treated with the anti-androgen, bicalutamide (Casodex). The number of beta-adrenergic receptors was modestly up-regulated in androgen independent cell lines (LNCaP-C4, LNCaP-C4-2 and DU145) compared to LNCaP. Triiodothyronine (T3) increased the level of beta(2)-AR and the effect of T3 was inhibited by bicalutamide. Immunohistochemical staining of human prostate specimens showed high expression of beta(2)-AR in glandular, epithelial cells and increased expression in malignant cells compared to benign hyperplasia and normal tissue. Interestingly, beta(2)-AR mRNA was strongly down-regulated by androgen ablation therapy of prostate cancer patients.


CONCLUSIONS
The level of beta(2)-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months.
Ramberg
Håkon
H
Faculty Division Aker University Hospital, University of Oslo, Oslo Urological University Clinic, Aker University Hospital, Oslo, Norway.
Eide
Turid
T
Krobert
Kurt Allen
KA
Levy
Finn Olav
FO
Dizeyi
Nishtman
N
Bjartell
Anders S
AS
Abrahamsson
Per-Anders
PA
Taskén
Kristin Austlid
KA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D015854:Up-Regulation
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D018343:Receptors, Adrenergic, beta-2; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D014284:Triiodothyronine; C053541:bicalutamide