Establishment and characterization of an androgen receptor-dependent, androgen-independent human prostate cancer cell line, LNCaP-CS10.
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.
Ishikura
Nobuyuki
N
Research Division, Kamakura Research Laboratories, Pharmaceutical Research Department 2, Chugai Pharmaceutical Co. Ltd., Kamakura, Kanagawa, Japan. ishikuranby@chugai-pharm.co.jp
Kawata
Hiromitsu
H
Nishimoto
Ayako
A
Nakamura
Ryo
R
Ishii
Nobuya
N
Aoki
Yuko
Y
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009570:Nitriles / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000502:physiology; D014105:Tosyl Compounds / Q000494:pharmacology*
D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D019947:Receptors, Interleukin-6; D014105:Tosyl Compounds; C053541:bicalutamide; D017430:Prostate-Specific Antigen