Transcriptional Roles of Nuclear Factor κB and Nuclear Factor-Interleukin-6 in the Tumor Necrosis Factor α-Dependent Induction of Cyclooxygenase-2 in MC3T3-E1 Cells

Yamamoto, Kei; Arakawa, Toshiya; Ueda, Natsuo; Yamamoto, Shozo

doi:10.1074/jbc.270.52.31315

Cited by 620 publications

(441 citation statements)

References 38 publications

Supporting

Mentioning

420

Contrasting

Unclassified

Order By: Relevance

“…We also show that diosgenin suppressed TNF-induced invasion by tumor cells, and this inhibition correlated with the downregulation of MMP-9 and COX-2. The role of MMP-9 and COX-2 in invasion has been demonstrated earlier (Yamamoto et al, 1995;Attiga et al, 2000;Esteve et al, 2002).…”

Section: Discussionmentioning

confidence: 66%

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

2005

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 66%

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

2005

View full text Add to dashboard Cite

“…TNFa has been shown to upregulate levels of NF-kB target genes like intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase (Cox-2), cyclin D1, Bcl-xL, FLICE-inhibitory protein (FLIP), etc. [22][23][24][25] We assessed whether R-Roscovitine could downregulate these endogenous NF-kB target genes in a manner similar to its repression of the NF-kB reporter gene activity ( Figure 1). Figure 3a and b (lanes 7-10) document that R-Roscovitine repressed the expression of NF-kB gene products ICAM-1, monocyte chemoattractant protein (MCP-1), Bcl-xL and FLIP in both A549 and H1299 cells.…”

Section: Resultsmentioning

confidence: 99%

R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy

Dey

Wong²,

Cheok

et al. 2007

Cell Death Differ

View full text Add to dashboard Cite

Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that is currently in phase II clinical trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate nuclear factor-kappa B (NF-jB) activation in response to tumor necrosis factor (TNF)a and interleukin 1. Activation of p53-dependent transcription is not compromised when RRoscovitine is combined with TNFa. We characterize the molecular mechanism governing NF-jB repression and show that RRoscovitine inhibits the IjB kinase (IKK) kinase activity, which leads to defective IjBa phosphorylation, degradation and hence nuclear function of NF-jB. We further show that the downregulation of the NF-jB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-jB target genes monocyte chemoattractant protein, intercellular adhesion molecule-1, cyclooxygenase-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFa and RRoscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anticancer drug that functions by simultaneously causing p53 activation and NF-jB suppression. This study also provides mechanistic insight into the molecular mechanism of action of R-Roscovitine, thereby possibly explaining its antiinflammatory properties. The p53 and nuclear factor-kappa B (NF-kB) pathways are two critical transcriptional regulatory networks deregulated in various human ailments including cancer and there has been a lot of evidence of cross-talk between these two pathways. 1 Activation of p53 is associated with cell cycle arrest and apoptosis while NF-kB activation is associated with cell survival. Hence, the cross-talk between these pathways must be finely tuned and regulated.p53 is one of the most extensively studied tumor suppressor proteins. 2 Loss or mutation of p53 function is correlated with increased cancer susceptibility. Hence, activating p53 has been a goal of several small molecule inhibitors currently being evaluated in the clinic.NF-kB is a transcription factor critical for the control of inflammation, apoptosis and cell proliferation. 3,4 Chronic inflammation by constitutively active NF-kB has been shown to contribute to the development of many cancers. 5 It is becoming apparent that deregulated activity of NF-kB is observed and causally linked to the development of several diseases that have an inflammatory component. 6,7 Hence, identification of NF-kB inhibitors has been the focus of several academic and pharmaceutical establishments. 6,7 Since p53 promotes cell death and NF-kB prevents cell death, an anticancer agent that simultaneously activates p53 and inhibits NF-kB would offer greater potential to target two cancer targets positively.One of the ways in which the p53 pathway has been successfully targeted is by using cyclin-dependent kinase (CDK) inhibi...

show abstract

“…NF-κB is known to regulate the expression of proinflammatory and proliferative markers, including iNOS [36], COX-2 [37], MMP-9 [38], and cyclin D1 [39]. To determine whether GSH can inhibit the curcumin to suppress these gene products, cells were pretreated with various concentrations of GSH for 2 h, treated with curcumin for 4 h, and then exposed to TNF.…”

Section: Glutathione Inhibits Curcumin-mediated Suppression Of Tnf-inmentioning

confidence: 99%

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

Sandur

Ichikawa

Pandey

et al. 2007

Free Radical Biology and Medicine

262

168

View full text Add to dashboard Cite

Extensive research within last half a century has indicated that curcumin (diferuloylmethane), a yellow pigment in curry powder, exhibits antioxidant, anti-inflammatory and proapoptotic activities. Whether anti-inflammatory and proapoptotic activities assigned to curcumin, are mediated through its antioxidant mechanism was investigated. We found that TNF-mediated NF-κB activation was inhibited by curcumin; and glutathione reversed the inhibition. Similarly, suppression of TNFinduced AKT activation by curcumin, was also abrogated by glutathione. The reducing agent also counteracted the inhibitory effect of curcumin on TNF-induced NF-κB regulated antiapoptotic (Bcl-2, Bcl-xL, IAP1), proliferative (cyclin D1) and proinflammatory (COX-2, iNOS and MMP-9) gene products. The suppression of TNF-induced AP-1 activation by curcumin was also reversed by glutathione. Also, the direct proapoptotic effects of curcumin were inhibited by glutathione and potentiated by depletion of intracellular glutathione by buthionine sulfoximine. Moreover, curcumin induced the production of reactive oxygen species (ROS) and modulated the intracellular GSH levels. Quenchers of hydroxyl radicals, however, were ineffective in inhibiting curcumin mediated NF-κB suppression. Further, N-acetylcysteine partially reversed the effect of curcumin. Based on these results we conclude that curcumin mediate its apoptotic and anti-inflammatory activities through modulation of the redox status of the cell.

show abstract

Transcriptional Roles of Nuclear Factor κB and Nuclear Factor-Interleukin-6 in the Tumor Necrosis Factor α-Dependent Induction of Cyclooxygenase-2 in MC3T3-E1 Cells

Cited by 620 publications

References 38 publications

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression

R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

Contact Info

Product

Resources

About