Nuclear Factor-κB Is Constitutively Activated in Prostate Cancer <b>
                     <i>In vitro</i>
                  </b> and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate

Sweeney, Christopher J.; Li, Lang; Shanmugam, Rajasubramaniam; Bhat‐Nakshatri, Poornima; Jayaprakasan, Vetrichelvan; Baldridge, Lee Ann; Gardner, Thomas A.; Smith, Martin; Nakshatri, Harikrishna; Liu, Cheng

doi:10.1158/1078-0432.ccr-0571-03

Cited by 150 publications

(140 citation statements)

References 22 publications

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“…Engagement of RAGE is known to trigger different signaling cascades, usually leading to activation of the transcription factor nuclear factor nB (25,26,43). Interestingly, overexpression of p65, the active subunit of nuclear factor nB, was found to occur as an early event in the development of prostate cancer (44). Furthermore, active nuclear factor nB was frequently detected in prostatic adenocarcinomas with perineural location and has been linked functionally to mechanisms that promote perineural invasion (45), which is the major mechanism of prostate cancer spread outside the prostate (46).…”

Section: Resultsmentioning

confidence: 99%

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

Hermani¹,

Heß

Servi³

et al. 2005

Clinical Cancer Research

225

158

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Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. Experimental Design:Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.

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Section: Resultsmentioning

confidence: 99%

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

Hermani¹,

Heß

Servi³

et al. 2005

Clinical Cancer Research

225

158

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“…Overall survival dependent on cytoplasmic (C and E) and nuclear (D and F) RelA overexpression for the whole study cohort (C and D) as well as for the subgroup of node-negative patients (E and F). Sweeney et al, 2004), endometrial (Pallares et al, 2004), hepatocellular (Tai et al, 2000) and oral (Nakayama et al, 2001) as well as cervical (Nair et al, 2003) carcinoma. Reports on RelA expression in pancreatic cancer are sparse.…”

Section: Discussionmentioning

confidence: 99%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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“…Constitutive NFjB activation and subsequent Bcl-2 increase mark hormone refractory PrCa. 42,56,57 Conversely, AR and NFjB counteract in transcription assays. 58 Indeed, reporter assays showed high basal NFjB activity in PC-3 cells, which was decreased upon transient transfection with AR WT and diminished further by DHT (Fig.…”

Section: Ar Activation Lowered Nfjb Levels and Activitymentioning

confidence: 99%

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

Nelius

Filleur

Yemelyanov

et al. 2007

Intl Journal of Cancer

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The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions. While androgen ablation drives the regression of normal and cancerous prostate, testosterone may cause both proliferation and apoptosis. Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor (AR), however no mechanistic explanation was offered. In this paper we demonstrate in vivo anti-tumor effect of the AR on prostate cancer growth and identify its molecular mediators. We analyzed the effect of AR on the tumorigenicity of prostate cancer cells. Unexpectedly, the AR-expressing cells formed tumors in male mice at a much lower rate than the AR-negative controls. Moreover, the AR-expressing tumors showed decreased vascularity and massive apoptosis. AR expression lowered the angiogenic potential of cancer cells, by increasing secretion of an anti-angiogenic protein, thrombospondin-1. AR activation caused a decrease in RelA, a subunit of the pro-survival transcription factor NFjB, reduced its nuclear localization and transcriptional activity. This, in turn, diminished the expression of its anti-apoptotic targets, Bcl-2 and IL-6. Increased apoptosis within AR-expressing tumors was likely due to the NFjB suppression, since it was restricted to the cells lacking nuclear (active) NFjB. Thus we for the first time identified combined decrease of NFjB and increased TSP1 as molecular events underlying the AR anti-tumor activity in vivo. Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal, a standard treatment for early-stage prostate cancer. ' 2007 Wiley-Liss, Inc.

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Nuclear Factor-κB Is Constitutively Activated in Prostate Cancer In vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate

Cited by 150 publications

References 22 publications

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

Calcium-Binding Proteins S100A8 and S100A9 as Novel Diagnostic Markers in Human Prostate Cancer

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

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