The androgen receptor pathway is by-passed in prostate cancer cells generated after prolonged treatment with bicalutamide.
BACKGROUND
Experimental work in various prostate cancer models revealed that the androgen receptor is frequently upregulated and implicated in tumor progression. However, little attention has been paid to the androgen receptor-signaling pathway in the development of therapy resistance in patients who receive chronic treatment with a non-steroidal anti-androgen.


METHODS
We have generated a novel subline, LNCaP-Bic, after prolonged treatment with androgen and bicalutamide in vitro. Proliferation of LNCaP-Bic cells in the absence or presence of androgen, tocopherol succinate, and/or bicalutamide was assessed by cell counting. Androgen receptor expression was determined by Western blot. Luciferase activity was measured in cells transfected with an androgen-responsive reporter.


RESULTS
In basal conditions, proliferation of LNCaP-Bic cells increased more than threefold over that of control LNCaP cells. Neither synthetic androgen R1881 nor bicalutamide showed any effect on LNCaP-Bic growth in vitro. Androgen receptor expression did not differ between the cell subline generated in the presence of bicalutamide and parental LNCaP cells. The ability of R1881 to induce reporter gene activity in LNCaP-Bic cells was reduced by 56%. Tocopherol succinate caused inhibition of proliferation only in the parental cell line although the androgen receptor and prostate-specific antigen were down regulated by the vitamin E derivative in both parental LNCaP and LNCaP-Bic cells.


CONCLUSIONS
Androgen receptor-mediated signal transaction is not enhanced in cells selected in the presence of bicalutamide. Our data may suggest that a more differentiated approach in targeting the androgen receptor is needed in prostate cancers that become resistant to classic endocrine treatment.
Hobisch
Alfred
A
Department of Urology, General Hospital Feldkirch, Feldkirch, Austria.
Fritzer
Andreas
A
Comuzzi
Barbara
B
Fiechtl
Matthias
M
Malinowska
Kamilla
K
Steiner
Hannes
H
Bartsch
Georg
G
Culig
Zoran
Z
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D014105:Tosyl Compounds; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide