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Purpose: Nuclear factor nB (NF-nB) is an important transcription factor in various biological processes. Constitutive NF-nB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear. Experimental Design: Constitutive NF-nB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-nB activation, we established cancer cells with stable knockdown of InB kinase g (NF-nB essential modulator), which is the regulatory subunit of the InB kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed. Results: Constitutive NF-nB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KD in vitro, whereas apoptosis mediated by tumor necrosis factor-a and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-nB activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KD (to 6%) than in WT (to 50%). Conclusion: NF-nB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-nB activation.Colorectal cancer is the second leading cause of cancer-related death in industrialized nations (1). The development of colorectal cancer results from the sequential accumulation of activating mutations in oncogenes, such as ras, and mutations, truncations, or deletions in the coding sequences of several tumor suppressor genes, including p53 and adenomatous polyposis coli (APC; ref. 2).Over the last decade, there has been a great deal of progress in the development of new therapies for the treatment of colorectal cancer. The cytotoxic chemotherapy drug 5-fluorouracil (FU) was reformulated, and two new drugs, oxaliplatin and irinotecan, have been investigated as adjunctive therapies. In addition, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatments for metastatic colorectal carcinoma (3, 4). However, many cases show tolerance of such treatments (3, 4). Therefore, it is necessary to develop new approaches to replace or complement current therapies.Nuclear factor nB (NF-nB) transcription factors are key regulators of innate immune responses, inflammation, and cell survival (5), and are assembled...

Inflammatory mediators such as TNF-α, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-κB. The aim of the present study was to investigate whether the NF-κB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IκB kinaseβ subunit (IKKβ) and inhibit NF-κB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-κB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-κB inhibition in both models. These results indicate that an IKKβ-targeted NF-κB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.

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