Aberrant rel/nfkb genes and activity in human cancer

Rayet, Béatrice; Gélinas, Céline

doi:10.1038/sj.onc.1203221

Cited by 1,048 publications

(816 citation statements)

References 119 publications

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“…Overexpression, amplification, and rearrangements of different genes related to NF-kB have been observed in tumors. 1 NF-kB is activated in response to various inflammatory stimuli including cytokines, mitogens, bacterial products, viral proteins, and apoptosis-inducing agents. 2,3 Although the primary level of NF-kB activation lies in the removal of the inhibitory subunit of NF-kB (inhibitory subunit of kappa B (IkBa)), the phosphorylation of p65 is required to recruit the transcriptional apparatus and to stimulate expression of several genes including cyclin D1, adhesion molecules, cyclooxygenase (Cox)-2, and matrix metalloproteinases.…”

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confidence: 99%

“…11 Higher activity of NF-kB is a common characteristic of many tumor cells. 1,2,12,13 HuT-78, a cutaneous lymphoid T cell line that constitutively expresses NF-kB, is resistant to TNFinduced apoptosis. 14,15 Constitutive activity of IKK, mediated by different factors like interleukin-1, epidermal growth factor, heregulin, and so on, has been shown in constitutive NF-kBexpressing cells.…”

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confidence: 99%

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Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

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The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P 3 -25) is known to possess antibacterial, anti-fungal, anti-tubercular, and local anesthetic activities. We studied the anti-tumorigenic activity of P 3 -25 and the role of nuclear transcription factor kappaB (NF-jB) in this process. In constitutive NF-jB-expressing cells, treatment with P 3 -25 inhibited the expression of NF-jB-dependent reporter gene, adhesion molecules, and cyclooxygenase. It downregulated phosphorylation of p65 by inhibiting upstream kinases, such as protein kinase A and casein kinase II, but did not alter NF-jB DNA-binding activity. Alone, P 3 -25 induced apoptosis in NF-jB-expressing and doxorubicin-resistant breast cancer cells, and in the presence of other chemotherapeutic agents, it potentiated apoptosis. Overall, our results suggest that P 3 -25 exerts antitumorigenic activity by inhibiting phosphorylation of p65, the transcriptionally active subunit of NF-jB by inhibiting its upstream kinases, and potentiates apoptosis mediated by chemotherapeutic agents. These results suggest novel approaches for designing of anticancer drugs for combination chemotherapy.

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confidence: 99%

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confidence: 99%

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Manna

Sarkar

2006

Cell Death Differ

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“…The transcriptional activity of these modified promoter systems remains at very low levels in the low CEAexpressing cancer cells (Richards et al, 1995a;Nyati et al, 2002). High NF-kB activity is a very common feature of cancers (Rayet and Gelinas, 1999). In this study, four linked NF-kB-binding sites in tandem (kB4) were exploited as a cancer-specific enhancer to improve the transcriptional activity of the CEA promoter.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of cancer-specific NF-κB-CEA enhancer–promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines

et al. 2007

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Nuclear factor-kappa B (NF-kB) is a transcription factor with high transcriptional activity in cancer cells. In this study, we developed a novel enhancer -promoter system, kB4-CEA205, in which the basal carcinoembryonic antigen (CEA) promoter sequence (CEA205) was placed downstream of the four tandem-linked NF-kB DNA-binding sites (kB4). In combination with a kB4 enhancer, the transcriptional activity of the CEA promoter was significantly enhanced (three-to eight-fold) in cancer cell lines but not in normal cells. In cancer cell lines, the transcriptional activity of kB4-CEA205 was comparable with that of the SV40 promoter. We also constructed vectors in which the thymidine phosphorylase (TP) cDNA was under the control of CEA205, kB4, kB4-CEA205 and CMV promoters, respectively. TP protein and enzyme activity were detected at comparable levels in kB4-CEA205-and CMV-driven TP cDNAtransfected cancer cell lines (H630 and RKO). The kB4-TP and CEA205-TP-transfected cell lines, respectively, only demonstrated negligible and low levels of TP protein and enzyme activity. Both CMV-and kB4-CEA205-driven TP cDNA transiently transfected cells were 8-to 10-fold sensitised to 5-fluorouracil (5-FU) prodrug, 5 0 -deoxy-5-fluorouradine (5 0 -DFUR), in contrast to only 1.5-to 2-fold sensitised by the kB4-and CEA205-driven TP cDNA-transfected cells. The bystander killing effect of CMV-and kB4-CEA205-driven TP cDNA-transfected cells was comparable. This is the first report that indicates that the NF-kB DNA-binding site could be used as a novel cancer-specific enhancer to improve cancer-specific promoter activity in gene-directed enzyme prodrug therapy. Lack of selectivity for malignant cells leading to dose-limiting toxicity is one of the major obstacles for the success of cancer chemotherapy. Gene-directed enzyme prodrug therapy (GDEPT) is potentially an elegant way to improve the therapeutic index of active anticancer drugs, but one of the major limitations for the clinical application of this approach is the lack of strong cancerspecific promoters (Aghi et al, 2000;Rooseboom et al, 2004).Carcinoembryonic antigen (CEA) is not expressed in normal and overexpressed in epithelial cancer cells (Shively and Beatty, 1985). Four cis-acting DNA-binding elements mapped on the CEA promoter region within 300 bp upstream of CEA translation starting point, especially, the first three elements are essential for specific CEA transcription (Hauck and Stanners, 1995;Richards et al, 1995a). Utilisation of the CEA promoter in an adenovirus vector for cytosine deaminase (CD) gene expression improves the selectivity of 5 0 -deoxy-5-fluorocytidine (5-DFCR)/5-fluorouracil (5-FU) conversion in CEA-expressing tumours (Richards et al, 1995a;Lan et al, 1996a). However, the transcriptional activity of CEA in most cancer cell lines is 10-to 300-fold lower than that of CMV and RSV viral promoters (Lan et al, 1996b;Ueda et al, 2001).Even when using adenovirus to deliver CEA promoter-driven suicide gene in vivo, few reports have demonstrated sufficient antitumou...

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“…The deregulation of RelA might be caused by altered intracellular signal transduction or chromosomal overrepresentation of the respective gene locus. And in fact RELA amplification has been described in various solid tumours (Rayet and Gelinas, 1999), but not in ductal pancreatic adenocarcinomas (Schleger et al, 2000).…”

Section: Shuklamentioning

confidence: 98%

“…Deregulated IKK and NF-kB activity contribute to tumorigenesis by triggering antiapoptotic and proproliferative responses (Rayet and Gelinas, 1999;Baldwin, 2001). Furthermore, activation of IKK and NF-kB may play an important role in cancer progression elicited by inflammatory cytokines (Karin and Greten, 2005).…”

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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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Aberrant rel/nfkb genes and activity in human cancer

Cited by 1,048 publications

References 119 publications

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

In vitro evaluation of cancer-specific NF-κB-CEA enhancer–promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines

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

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