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Morin (3,5,7,2',4'-Pentahydroxyflavone) Abolishes Nuclear Factor-B Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-B–Regulated Gene Expression and Up-regulation of Apoptosis

Authors' Affiliations: ¹ Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center; ² Molecular Neurotoxicology Laboratory/Proteomics Core, Department of Biology, Texas Southern University, Houston, Texas; and ³ Laboratory of Immunology, Center for DNA Fingerprinting and Diagnostics, Nacharam, Hyderabad, India 500 076.

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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-B (NF-B) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-B activation.

Experimental Design: We investigated the effect of morin on NF-B pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-B–regulated gene products involved in cell survival, proliferation, and invasion was also examined.

Results: We showed by DNA-binding assay that NF-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-B by morin was mediated through inhibition of IB (inhibitory subunit of NF-B) kinase, leading to suppression of phosphorylation and degradation of IB and consequent p65 nuclear translocation. Morin also inhibited the NF-B–dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-B–inducing kinase, IB kinase, and the p65 subunit of NF-B. NF-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-B and NF-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.