Document Detail

Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant prostate cancer.
MedLine Citation:
PMID:  23038213     Owner:  NLM     Status:  MEDLINE    
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.
Jordi Codony-Servat; Mercedes Marín-Aguilera; Laura Visa; Xabier García-Albéniz; Estela Pineda; Pedro L Fernández; Xavier Filella; Pere Gascón; Begoña Mellado
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-04
Journal Detail:
Title:  The Prostate     Volume:  73     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-05-10     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  512-21     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Medical Oncology Department and Laboratory of Translational Oncology, Hospital Clínic-Fundació Clínic per a la recerca Biomèdica, Barcelona, Spain.
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MeSH Terms
Adenocarcinoma / drug therapy*,  genetics,  surgery
Aged, 80 and over
Androgens / deficiency
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Combined Modality Therapy
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic / physiology
Interleukin-6 / blood,  genetics*
Interleukin-8 / blood,  genetics
Middle Aged
Prostatic Neoplasms / drug therapy*,  genetics,  surgery
RNA, Small Interfering / genetics
Taxoids / therapeutic use*
Transcription Factor RelA / genetics*,  metabolism
Reg. No./Substance:
0/Androgens; 0/Antineoplastic Agents; 0/IL6 protein, human; 0/IL8 protein, human; 0/Interleukin-6; 0/Interleukin-8; 0/RNA, Small Interfering; 0/Taxoids; 0/Transcription Factor RelA; 15H5577CQD/docetaxel

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