Abstract
Nuclear factor kappaB (NF-kappaB) is an important transcription factor in various biological processes. Constitutive NF-kappaB activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear. Constitutive NF-kappaB activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-kappaB activation, we established cancer cells with stable knockdown of IkappaB kinase gamma (NF-kappaB essential modulator), which is the regulatory subunit of the IkappaB 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. Constitutive NF-kappaB 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-alpha 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-kappaB 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%). NF-kappaB inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-kappaB activation.
Highlights
Nuclear factor nB (NF-nB) is an important transcription factor in various biological processes
We examined whether NF-nB was constitutively active in colorectal carcinoma cell lines by electrophoretic mobility shift assay (Fig. 1B)
These results suggest that constitutive activation of NF-nB occurs frequently in colorectal carcinoma
Summary
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. Experimental Design: Constitutive NF-nB activation was evaluated in colorectal cancer tissues and cell lines. Results: Constitutive NF-nB activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. 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. 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 Most NF-nB dimers are bound to specific inhibitory proteins, InBs, in the cytoplasm Many proinflammatory stimuli, such as tumor necrosis factor-a (TNFa), lipopolysaccharide, and various drugs, can activate NF-nB, primarily through InB kinase (IKK)-dependent phosphorylation and degradation of the InB inhibitory proteins.
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