期刊
CLINICAL CANCER RESEARCH
卷 13, 期 7, 页码 2290-2297出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-06-2394
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资金
- NCI NIH HHS [P01 CA091844, CA91844] Funding Source: Medline
- NCRR NIH HHS [G12 RR003045-180001, G12 RR003045, 5G12 RR 003045-19] Funding Source: Medline
Purpose: Morin is a flavone that exhibits antiproliferative, antitumor, and anti-inflammatory effects through a mechanism that is not well understood. Because of the role of transcription factor nuclear factor-kappa B (NF-kappa B) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-kappa B activation. Experimental Design: We investigated the effect of morin on NF-kappa B pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-kappa B-regulated gene products involved in cell survival, proliferation, and invasion was also examined. Results: We showed by DNA-binding assay that NF-kappa B activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, lipopolysaccharide, ceramide, interleukin-1, and H2O2 was suppressed by morin; the suppression was not cell type specific. The suppression of NF-kappa B by morin was mediated through inhibition of I kappa B alpha (inhibitory subunit of NF-kappa B) kinase, leading to suppression of phosphorylation and degradation of I kappa B alpha and consequent p65 nuclear translocation. Morin also inhibited the NF-kappa B - dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-kappa B-inducing kinase, I kappa B kinase, and the p65 subunit of NF-kappa B. NF-kappa B - regulated gene products involved in cell survival [inhibitor of apoptosis (IAP) 1, IAP2, X chromosome-linked IAP, Bcl-xL, and survivin], proliferation (cyclin D1 and cyclooxygenase-2), and invasion (matrix metalloproteinase-9) were down-regulated by morin. These effects correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Conclusion: Overall, our results indicate that morin suppresses the activation of NF-kappa B and NF-kappa B-regulated gene expression, leading to enhancement of apoptosis. This may provide the molecular basis for the ability of morin to act as an anticancer and anti-inflammatory agent.
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