Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

Abstract

Nuclear factor (NF)-kB/p65 regulates the transcription of a wide variety of genes involved in cell survival, invasion and metastasis. We characterised by immunohistochemistry the expression of NF-kB/p65 protein in six histologically normal prostate, 13 high-grade prostatic intraepithelial neoplasia (PIN) and 86 prostate adenocarcinoma specimens. Nuclear localisation of p65 was used as a measure of NF-kB active state. Nuclear localisation of NF-kB was only seen in scattered basal cells in normal prostate glands. Prostatic intraepithelial neoplasias exhibited diffuse and strong cytoplasmic staining but no nuclear staining. In prostate adenocarcinomas, cytoplasmic NF-kB was detected in 57 (66.3%) specimens, and nuclear NF-kB (activated) in 47 (54.7%). Nuclear and cytoplasmic NF-kB staining was not correlated (P ¼ 0.19). By univariate analysis, nuclear localisation of NF-kB was associated with biochemical relapse (P ¼ 0.0009; log-rank test) while cytoplasmic expression did not. On multivariate analysis, serum preoperative prostate specific antigen (P ¼ 0.02), Gleason score (P ¼ 0.03) and nuclear NF-kB (P ¼ 0.002) were independent predictors of biochemical relapse. These results provide novel evidence for NF-kB/p65 nuclear translocation in the transition from PIN to prostate cancer. Our findings also indicate that nuclear localisation of NF-kB is an independent prognostic factor of biochemical relapse in prostate cancer.

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…Although our study did not investigate the potential causal relationship between NF-kB activation and EMT, this last phenomenon was found to be highly relevant in resistance to therapy. Moreover, increased nuclear NF-kB (RELA staining) correlated with a shorter time to clinical relapse, confirming the prognostic value of this pathway activation in prostate cancer (22).…”

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

“…Constitutive activity of NF-kB has been reported in CaP cell lines and/or biopsy tissue and is associated with regulating the expression of genes that induce cell proliferation and/or underpin cell survival (Huang et al, 2001;Fradet et al, 2004;Ross et al, 2004;Shukla et al, 2004;Sweeney et al, 2004;Domingo-Domenech et al, 2005). However, despite suppressing the constitutive activity of the NF-kB transcription factor, DEX administration failed to reduce the proliferation or the viability of PC3 tumour cells or hBMECs.…”

“…Constitutive activation of the NF-kB transcription factor has been reported in CaP and is associated with disease progression, chemoresistance, angiogenesis and metastasis (Huang et al, 2001;Fradet et al, 2004;Ross et al, 2004;Shukla et al, 2004;Sweeney et al, 2004;Domingo-Domenech et al, 2005). Nuclear factor-kB has been reported to induce the transcription of proinflammatory genes, many of which have been implicated in each of the above phenotypes.…”

YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia

“…Although the percentage of positive nuclear staining in tumor specimens varied between 15-54.7% in different studies (Lessard et al, 2003;Ross et al, 2004;Domingo-Domenech et al, 2005;Lessard et al, 2005), emerging data suggest NF-kB nuclear localization links to poor clinical outcome (Lessard et al, 2003;Ayala et al, 2004;Fradet et al, 2004). In particular, constitutive NF-kB activity correlates with progression to bone metastasis (Lessard et al, 2003).…”