Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Charalambous, Michalis P.; Maihöfner, Christian; Bhambra, Upinder; Lightfoot, T.; Gooderham, Nigel J.

doi:10.1038/sj.bjc.6600927

Cited by 74 publications

(70 citation statements)

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“…These results are in agreement with earlier studies, that found both stromal and epithelial colorectal cells expressing COX-2 in colorectal adenomas (Arnoletti et al, 2005;Pisano et al, 2005;Tatsu et al, 2005) and carcinomas (Battu et al, 1998;Yamashita et al, 2003;Ohta et al, 2006). We have reported earlier (Charalambous et al, 2003), a significant increase of COX-2 expression in malignant colorectal epithelial cells, compared with adjacent normal epithelium. We now report that this difference is not observed in stromal cells.…”

Section: Discussionsupporting

confidence: 83%

“…We have shown earlier that upregulation of COX-2 is accompanied by increased expression of NF-kB-p65 and IKKa in malignant colorectal epithelial cells (Charalambous et al, 2003), supporting the proposal that NF-kB is involved in COX-2 induction in these cells. This was in agreement with earlier model systems that showed expression of COX-2 was mediated by NF-kB in human umbilical vein (Jones et al, 1993) and rheumatoid synoviocytes (Crofford et al, 1997).…”

Section: Discussionsupporting

confidence: 59%

“…In vitro inhibition of this protein has been shown to attenuate COX-2 expression in colorectal cancer cells, indicating that NF-kB may play an important role in COX-2 induction (Plummer et al, 1999;Williams et al, 2003). Earlier, we have shown that upregulation of COX-2 is accompanied by increased expression of NF-kB-p65 and IkB-kinase-alpha (IKKa) in human colorectal cancer epithelial cells (Charalambous et al, 2003).…”

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confidence: 99%

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Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

et al. 2009

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BACKGROUND: Cyclooxygenase-2 (COX-2) is selectively over-expressed in colorectal tumours. The mechanism of COX-2 induction in these tumours is not fully understood, although evidence suggests a possible link between nuclear factor (NF)-kB and COX-2. We hypothesised an association between COX-2 expression and NF-kB-p65, NF-kB-p50 and IkB-kinase-a (IKKa) in both epithelial and stromal cells in human colorectal cancer. METHODS: Using immunohistochemistry, we measured COX-2, NF-kB-p65, NF-kB-p65 nuclear localisation sequence (NLS), NF-kBp50, NF-kB-p50 NLS and IKKa protein expression in matched colorectal biopsy samples comprising both non-tumour and adjacent tumour tissue from 32 patients with colorectal cancer. RESULTS: We have shown that stromal cells of malignant and surrounding normal colorectal tissue express COX-2. In all cell types of malignant tissue, and in vascular endothelial cells (VECs) of neighbouring normal tissue, COX-2 expression was strongly associated with NF-kB-p65 expression (Pearson's correlation, P ¼ 0.019 for macrophages, P ¼ 0.001 for VECs, P ¼ 0.002 for fibroblasts (malignant tissue), and P ¼ 0.011 for VECs (non-malignant tissue)) but not NF-kB-p50 or IKKa. CONCLUSIONS: These data suggest that in these cells COX-2 induction may be mediated through activation of the canonical NF-kB pathway. Finally, the lack of association between COX-2, NF-kB-p65 or IKKa in stromal cells with the clinical severity of colorectal cancer as determined by Duke's stage, suggests that COX-2, NF-kB-p65 and IKKa expression are possibly early post-initiation events, which could be involved in tumour progression.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 59%

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confidence: 99%

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Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

et al. 2009

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“…Increased NFkB activity has been observed in CRC (Hardwick et al, 2001) and relative resistance to apoptosis has been attributed to high constitutive NFkB activity in other cancers (Bours et al, 1994;Lind et al, 2001;Charalambous et al, 2003). However, we found no evidence that the specificity of the aspirin-NFkB response is related to differential expression of basal IkBa or p65 proteins or their relative expression.…”

Section: Discussioncontrasting

confidence: 60%

Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis

2004

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Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) to a greater degree than other non-gastrointestinal cancers, but the molecular basis for this difference is unknown. We previously reported that aspirin induces signal-specific IkBa degradation followed by NFkB nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. Here, we explored the hypothesis that cell-type specific effects on NFkB signalling are responsible for the observed differences in protection by aspirin against CRC compared to breast and gynaecological cancers. We also assessed whether COX-2 expression, mutation status of adenomatous polyposis coli (APC), b-catenin, p53, or DNA mismatch repair (MMR) genes in CRC lines influenced aspirin-induced effects. We found that aspirin induced concentration-dependent IkBa degradation, NFkB nuclear translocation and apoptosis in all CRC lines studied. However, there was no such effect on the other cancer cell types, indicating a considerable degree of cell-type specificity. The lack of effect on NFkB signalling, paralleled by absence of an apoptotic response to aspirin in non-CRC lines, strongly suggests a molecular rationale for the particular protective effect of NSAIDs against CRC. Effects on NFkB and apoptosis were observed irrespective of COX-2 expression, or mutation status in APC, b-catenin, p53 and DNA MMR genes, underscoring the generality of the aspirin effect on NFkB in CRC cells. These findings raise the possibility of cell-type specific targets for the development of novel chemopreventative agents.

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“…Overexpression of COX-2 is sufficient to induce tumorigenesis or sensitize mouse skin for carcinogenesis (39,40). Cyclooxygenase-2 expression is regulated through multiple pathways including NF-B, C/EBP transcription factors, and mitogen-activated protein kinases (41)(42)(43)(44)(45)(46). Induction of COX-2 mRNA is regulated by NF-B in macrophages (41)(42)(43)(44).…”

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confidence: 99%

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

Hung

Lei³

et al. 2004

Journal of Biological Chemistry

240

215

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Expression of mutant proteins or viral infection mayinterfere with proper protein folding activity in the endoplasmic reticulum (ER). Several pathways that maintain cellular homeostasis were activated in response to these ER disturbances. Here we investigated which of these ER stress-activated pathways induce COX-2 and potentially oncogenesis. Tunicamycin and brefeldin A, two ER stress inducers, increased the expression of COX-2 in ML-1 or MCF-7 cells. Nuclear translocation of NF-B and activation of pp38 MAPK were observed during ER stress. I B␣ kinase inhibitor Bay 11-7082 or I B␣ kinase dominant negative mutant significantly inhibited the induction of COX-2. pp38 MAPK inhibitor SB203580 or eIF2␣ phosphorylation inhibitor 2-aminopurine attenuated the nuclear NF-B DNA binding activity and COX-2 induction. Expression of mutant hepatitis B virus (HBV) large surface proteins, inducers of ER stress, enhanced the expression of COX-2 in ML-1 and HuH-7 cells. Transgenic mice showed higher expression of COX-2 protein in liver and kidney tissue expressing mutant HBV large surface protein in vivo. Similarly, increased expression of COX-2 mRNA was observed in human hepatocellular carcinoma tissue expressing mutant HBV large surface proteins. In ML-1 cells expressing mutant HBV large surface protein, anchorage-independent growth was enhanced, and the enhancement was abolished by the addition of specific COX-2 inhibitors. Thus, ER stress due either to expression of viral surface proteins or drugs can stimulate the expression of COX-2 through the NF-B and pp38 kinase pathways. Our results provide important insights into cellular carcinogenesis associated with latent endoplasmic reticulum stress.

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Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Cited by 74 publications

References 46 publications

Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

Expression of COX-2, NF-κB-p65, NF-κB-p50 and IKKα in malignant and adjacent normal human colorectal tissue

Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

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