Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer.
Prostate
; 73(5): 512-21, 2013 Apr.
Article
em En
| MEDLINE
| ID: mdl-23038213
ABSTRACT
BACKGROUND:
Previous work showed that the NF-κB survival pathway is activated by docetaxel (D) and contributes to D resistance in prostate cancer. In this study we aimed to investigate the dynamics of the relationship between NF-κB and IL-6 in the shift from D-naive castration-resistant prostate cancer (CRPC) to D-resistance in patients and cell lines.METHODS:
CRPC tumor samples were tested for NF-κB/p65 and IL-6 by immunohistochemistry. CRPC patients treated with D were also tested for serum IL-6 (ELISA). Two D-resistant cell lines, PC-3R and DU-145R, derived from the CRPC cells PC-3 and DU-145, respectively, were tested for NF-κB activation (EMSA), NF-κB-related genes expression (RT-PCR), NF-κB inhibition (p65 siRNA) and IL-6 and IL-8 soluble levels (ELISA).RESULTS:
In CRPC patients treated with D (n = 72), pre-treatment IL-6 level correlated with nuclear NF-κB/p65 tumor staining and response to D, and was an independent prognostic factor for overall survival. However, IL-6 level changes under treatment did not correlate with clinical outcome. In PC-3 and DU-145 parental CRPC cells, as well as in D-resistant counterparts, D treatment induced NF-κB activation. In fact, NF-κB inhibition was sufficient to re-sensitize DU-145R cells to D. Despite enhanced NF-κB activity, IL-6 secretion in D-resistant cell lines was reduced and not induced by D treatment. The same occurred with IL-8 cytokine.CONCLUSIONS:
These preclinical and clinical results support a role of NF-κB and IL-6 in the resistance to D in CRPC, and support the investigation of targeted therapies to enhance the antitumor activity of D in this patient population.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Orquiectomia
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Adenocarcinoma
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Interleucina-6
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Taxoides
/
Fator de Transcrição RelA
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Aged80
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Prostate
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Espanha