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Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer

Authors

  • Jordi Codony-Servat,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Mercedes Marín-Aguilera,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Laura Visa,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Xabier García-Albéniz,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Estela Pineda,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Pedro L. Fernández,

    1. Pathology Department, Hospital Clínic, Barcelona. Spain
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  • Xavier Filella,

    1. Biochemistry Department, Hospital Clínic, Barcelona, Spain
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  • Pere Gascón,

    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
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  • Begoña Mellado

    Corresponding author
    1. Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain
    • Medical Oncology Department and Genitourinary Cancer Unit, Hospital Clínic Villarroel 170, 08036 Barcelona, Spain.
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  • No potential conflicts of interest are reported.

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. Prostate 73: 512–521, 2013. © 2012 Wiley Periodicals, Inc.

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