TY - JOUR
T1 - Morin (3,5,7,2′,4′-pentahydroxyflavone) abolishes nuclear factor-κB activation induced by various carcinogens and inflammatory stimuli, leading to suppression of nuclear factor-κB - Regulated gene expression and up-regulation of apoptosis
AU - Manna, Sunil K.
AU - Aggarwal, Rishi S.
AU - Sethi, Gautam
AU - Aggarwal, Bharat B.
AU - Ramesh, Govindarajan T.
PY - 2007/4/1
Y1 - 2007/4/1
N2 - 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-κB (NF-κB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-κB activation. Experimental Design: We investigated the effect of morin on NF-κB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-κB - regulated gene products involved in cell survival, proliferation, and invasion was also examined. Results: We showed by DNA-binding assay that NF-κB 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-κB by morin was mediated through inhibition of IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα and consequent p65 nuclear translocation. Morin also inhibited the NF-κB - dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-κB - inducing kinase, IκB kinase, and the p65 subunit of NF-κB. NF-κB - 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-κB and NF-κB-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.
AB - 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-κB (NF-κB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-κB activation. Experimental Design: We investigated the effect of morin on NF-κB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-κB - regulated gene products involved in cell survival, proliferation, and invasion was also examined. Results: We showed by DNA-binding assay that NF-κB 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-κB by morin was mediated through inhibition of IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα and consequent p65 nuclear translocation. Morin also inhibited the NF-κB - dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-κB - inducing kinase, IκB kinase, and the p65 subunit of NF-κB. NF-κB - 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-κB and NF-κB-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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U2 - 10.1158/1078-0432.CCR-06-2394
DO - 10.1158/1078-0432.CCR-06-2394
M3 - Article
C2 - 17404114
AN - SCOPUS:34247477985
SN - 1078-0432
VL - 13
SP - 2290
EP - 2297
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -