Gene interactions and pathways from curated databases and text-mining
Mol Pharmacol 2006, PMID: 16219905

Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation.

Aggarwal, Sita; Ichikawa, Haruyo; Takada, Yasunari; Sandur, Santosh K; Shishodia, Shishir; Aggarwal, Bharat B

Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor-kappaB (NF-kappaB), we have postulated that curcumin mediates its activity by modulating NF-kappaB activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-kappaB activation induced by a variety of agents (J Biol Chem 270:24995-50000, 1995). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-kappaB and NF-kappaB-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF-kappaB activation. Curcumin inhibited TNF-induced NF-kappaB-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-kappaB-inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB. Such TNF-induced NF-kappaB-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x(L), Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNF-induced nuclear translocation of p65, which corresponded with the sequential suppression of IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF-kappaB activation. Overall, our results indicated that curcumin inhibits NF-kappaB activation and NF-kappaB-regulated gene expression through inhibition of IKK and Akt activation.

Diseases/Pathways annotated by Medline MESH: Neoplasm Metastasis
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Text Mining Data

NF-kappaB → tumor necrosis factor (TNF): " Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF) induced NF-kappaB activation "

NF-kappaB → tumor necrosis factor receptor (TNFR)1: " Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1 , TNFR2, NF-kappaB inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB "

NF-kappaB → (TNFR)1: " Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1 , TNFR2, NF-kappaB inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB "

NF-kappaB → TNFR2: " Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2 , NF-kappaB inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB "

NF-kappaB → IkappaB kinase complex (IKK): " Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-kappaB inducing kinase, IkappaB kinase complex (IKK) , and the p65 subunit of NF-kappaB "

vascular endothelial growth factor → TNF: " Such TNF induced NF-kappaB regulated gene products involved in cellular proliferation [ cyclooxygenase-2 (COX-2), cyclin D1, and c-myc ], antiapoptosis [ inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome linked IAP, Bcl-2, Bcl-x ( L ), Bfl-1/A1, TNF receptor associated factor 1, and cellular Fas associated death domain protein-like interleukin-1beta converting enzyme inhibitory protein-like inhibitory protein ], and metastasis ( vascular endothelial growth factor , matrix metalloproteinase-9, and intercellular adhesion molecule-1 ) were also down-regulated by curcumin "

cyclin D1 → TNF: " Such TNF induced NF-kappaB regulated gene products involved in cellular proliferation [ cyclooxygenase-2 (COX-2), cyclin D1 , and c-myc ], antiapoptosis [ inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome linked IAP, Bcl-2, Bcl-x ( L ), Bfl-1/A1, TNF receptor associated factor 1, and cellular Fas associated death domain protein-like interleukin-1beta converting enzyme inhibitory protein-like inhibitory protein ], and metastasis ( vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1 ) were also down-regulated by curcumin "

intercellular adhesion molecule-1 → TNF: " Such TNF induced NF-kappaB regulated gene products involved in cellular proliferation [ cyclooxygenase-2 (COX-2), cyclin D1, and c-myc ], antiapoptosis [ inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome linked IAP, Bcl-2, Bcl-x ( L ), Bfl-1/A1, TNF receptor associated factor 1, and cellular Fas associated death domain protein-like interleukin-1beta converting enzyme inhibitory protein-like inhibitory protein ], and metastasis ( vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1 ) were also down-regulated by curcumin "

cyclin → TNF: " Such TNF induced NF-kappaB regulated gene products involved in cellular proliferation [ cyclooxygenase-2 (COX-2), cyclin D1, and c-myc ], antiapoptosis [ inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome linked IAP, Bcl-2, Bcl-x ( L ), Bfl-1/A1, TNF receptor associated factor 1, and cellular Fas associated death domain protein-like interleukin-1beta converting enzyme inhibitory protein-like inhibitory protein ], and metastasis ( vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1 ) were also down-regulated by curcumin "

[ cyclooxygenase-2 → TNF: " Such TNF induced NF-kappaB regulated gene products involved in cellular proliferation [ cyclooxygenase-2 (COX-2), cyclin D1, and c-myc ], antiapoptosis [ inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome linked IAP, Bcl-2, Bcl-x ( L ), Bfl-1/A1, TNF receptor associated factor 1, and cellular Fas associated death domain protein-like interleukin-1beta converting enzyme inhibitory protein-like inhibitory protein ], and metastasis ( vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1 ) were also down-regulated by curcumin "

COX-2 → TNF: " COX-2 promoter activity induced by TNF was abrogated by curcumin "

p65 → TNF: " We found that curcumin suppressed TNF induced nuclear translocation of p65 , which corresponded with the sequential suppression of IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation "

IKK → TNF: " Curcumin also inhibited TNF induced Akt activation and its association with IKK "

Akt → TNF: " Curcumin also inhibited TNF induced Akt activation and its association with IKK "

NF-kappaB → TNF: " Glutathione and dithiothreitol reversed the effect of curcumin on TNF induced NF-kappaB activation "

Manually curated Databases

No curated data.