Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline.
Cancer Res
; 63(17): 5622-8, 2003 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-14500404
ABSTRACT
Bone metastasis is commonly found in prostate cancer (PC) patients. Although the mechanisms for the recurrence of bone metastasis-derived PC during medical or surgical castration therapy are still unclear because of the lack of suitable experimental models, one hypothesis is that enhanced androgen receptor (AR) signaling causes androgen-refractory PC growth. To test this hypothesis, we first established a novel androgen-refractory MDA PCa 2b cell subline, MDA PCa 2b-hr, which was generated in vitro from bone metastasis-derived, androgen-dependent MDA PCa 2b human PC cells after approximately 35 weeks of growth suppression by androgen-depletion treatment to mimic the clinical PC recurrence during androgen-ablation therapy. The changes of the androgen responsiveness of growth and the AR expression levels during the transition from an androgen-dependent to androgen-refractory proliferative phase through a temporal growth-suppressed phase precisely paralleled that of the basal growth rate. Furthermore, the androgen-refractory growth of MDA PCa 2b-hr cells in androgen-depleted medium was suppressed by an antiandrogen, bicalutamide. Next, we established nude mouse xenograft models to clarify whether AR signaling in MDA PCa 2b-hr cells is also enhanced in vivo. Both the MDA PCa 2b and MDA PCa 2b-hr tumors grew in gonadally intact mice, but only the MDA PCa 2b-hr tumors grew in castrated mice. The growth rate of MDA PCa 2b-hr tumors was significantly higher in gonadally intact mice than in castrated mice. Treatment with dehydroepiandrosterone pellets, which produced clinical castration levels of serum testosterone, accelerated the MDA PCa 2b-hr but not MDA PCa 2b tumor growth in castrated mice and increased blood prostate-specific antigen levels in castrated mice bearing MDA PCa 2b-hr tumors but not in mice bearing MDA PCa 2b tumors. Our data suggest that the enhanced AR signaling should be closely correlated with the androgen-refractory growth of human bone metastasis-derived PC, which might come to use adrenal androgens remaining in the blood even after castration therapy and warrant the continuation of hormone therapy for the recurrent PC.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Receptores Androgênicos
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Androgênios
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Neoplasias Hormônio-Dependentes
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Japão