Background: Hormone refractoriness is a lethal event for advanced prostate cancer patients, but the mechanisms of the disease are not well elucidated, especially for the so-called "outlaw" pathways of androgen receptor (AR)-dependent, androgen-independent hormone-refractory prostate cancer.
Methods: Androgen-dependent prostate cancer LNCaP cells were treated with bicalutamide under an androgen-depleted condition to obtain refractory cells. In the obtained cell line, LNCaP-CS10, we analyzed the effects of androgen and bicalutamide on cell growth and prostate-specific antigen (PSA) production. In addition, AR gene mutation, AR expression levels, and AR subcellular localizations were analyzed.
Results: In LNCaP-CS10, cell growth and PSA production were found under an androgen-depleted condition and were induced by both R1881 and bicalutamide. Knocking down AR by siRNAs did suppress the growth and PSA production of LNCaP-CS10 cells in the androgen-depleted condition. In comparison to LNCaP, amplification or additional new mutations were not found in the AR genes, but AR nuclear translocation induced by bicalutamide was identified in the LNCaP-CS10 cells. The growth and PSA production of xenografted LNCaP-CS10 tumors, which secrete PSA not only in non-castrated SCID mice but also in castrated SCID mice, were not inhibited by bicalutamide.
Conclusions: We have generated a bicalutamide-resistant and androgen-independent prostate cancer cell line, LNCaP-CS10, with outlaw activation both in vitro and in vivo. The LNCaP-CS10 cell line is beneficial for elucidating outlaw pathway mechanisms and evaluating the efficacy of new therapeutics for hormone-refractory prostate cancer.
(c) 2009 Wiley-Liss, Inc.