Journal
PROSTATE
Volume 70, Issue 7, Pages 745-754Publisher
WILEY-LISS
DOI: 10.1002/pros.21107
Keywords
LNCaP; prostate cancer; anti-androgen; hormone refractory
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BACKGROUND. Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status. However, the mechanism of bicalutamide resistance remains unclear because few cell models have been generated. METHODS. We generated a bicalutamide-resistant subline, LNCaP-BC2, from LNCaP after prolonged treatment with bicalutamide. Androgen and /or bicalutamide responsiveness for proliferation and prostate-specific antigen (PSA) secretion were examined in vitro and in vivo. Testosterone and dihydrotestosterone (DHT) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry. Androgen receptor (AR) gene mutation and amplification and AR and pAR(210) expression were determined. RESULTS. LNCaP-BC2 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCa P. LNCaP-BC2 grew in castrated male mice, and the DHT level in grafted LNCaP-BC2 tumors was 7.7-fold lower than in LNCaP tumors. Bicalutamide stimulated LNCaP-BC2 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP-BC2 was weaker than that of LNCaP in vivo. Additional AR mutation and AR gene amplification were not detected in LNCaP-BC2, but AR and pAR(210) expression and PSA secretion in LNCaP-BC2 were higher than in LNCaP. CONCLUSIONS. Bicalutamide-resistant LNCaP-BC2 exhibited AR overexpression and hypersensitivity to low levels of androgen. Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion. In addition, pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP-BC2. Prostate 70: 745-754, 2010. (C) 2010 Wiley-Liss, Inc.
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