Evidence That Receptor Activator of Nuclear Factor (NF)-κB Ligand Can Suppress Cell Proliferation and Induce Apoptosis through Activation of a NF-κB-independent and TRAF6-dependent Mechanism

Bharti, Alok C.; Takada, Yasunari; Shishodia, Shishir; Aggarwal, Bharat B.

doi:10.1074/jbc.m308062200

Cited by 98 publications

(93 citation statements)

References 77 publications

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“…Briefly, KBM-5 cells were preincubated with various concentrations of GSH for 2 h, and then curcumin (50 μM) was added. After treatment with curcumin for 24 h at 37 °C, [24] cells were washed in phosphate-buffered saline, resuspended in 100 μl of binding buffer containing FITC-conjugated anti-annexin V antibody, and analyzed by flow cytometry (FACSCalibur; BD Biosciences). Data were collected from at least 10,000 cells at a flow rate of 250-300 cells/s.…”

Section: Annexin V Assaymentioning

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

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269

172

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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.

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Section: Annexin V Assaymentioning

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

Self Cite

269

172

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“…This assay uses calcein, a polyanionic dye, which is retained in live cells and provides green fluorescence (22). It also uses the ethidium monomer dye (red fluorescence), which can enter cells only through damaged membranes and bind to nucleic acids but is excluded by the intact plasma membrane of live cells.…”

Section: Live/dead Assaymentioning

confidence: 99%

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Ahn

Sethi

Aggarwal

2007

The Journal of Immunology

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101

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Numerous recent reports suggest that statins (hydroxy-3-methylglutaryl-CoA reductase inhibitors) exhibit potential to suppress tumorigenesis through a mechanism that is not fully understood. Therefore, in this article, we investigated the effects of simvastatin on TNF-α-induced cell signaling. We found that simvastatin potentiated the apoptosis induced by TNF-α as indicated by intracellular esterase activity, caspase activation, TUNEL, and annexin V staining. This effect of simvastatin correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1 and cyclooxygenase-2), cell survival (Bcl-2, Bcl-xL, cellular FLIP, inhibitor of apoptosis protein 1, inhibitor of apoptosis protein 2, and survivin), invasion (matrix mellatoproteinase-9 and ICAM-1), and angiogenesis (vascular endothelial growth factor); all known to be regulated by the NF-κB. We found that simvastatin inhibited TNF-α-induced NF-κB activation, and l-mevalonate reversed the suppressive effect, indicating the role of hydroxy-3-methylglutaryl-CoA reductase. Simvastatin suppressed not only the inducible but also the constitutive NF-κB activation. Simvastatin inhibited TNF-α-induced IκBα kinase activation, which led to inhibition of IκBα phosphorylation and degradation, suppression of p65 phosphorylation, and translocation to the nucleus. NF-κB-dependent reporter gene expression induced by TNF-α, TNFR1, TNFR-associated death domain protein, TNFR-associated factor 2, TGF-β-activated kinase 1, receptor-interacting protein, NF-κB-inducing kinase, and IκB kinase β was abolished by simvastatin. Overall, our results provide novel insight into the role of simvastatin in potentially preventing and treating cancer through modulation of IκB kinase and NF-κB-regulated gene products.

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“…This loss of membrane asymmetry can be detected by utilizing the binding properties of annexin V. This assay was performed as indicated previously (32).…”

Section: Methodsmentioning

confidence: 99%

Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Suppresses NF-κB Activation and NF-κB-regulated Gene Products Through Modulation of p65 and IκBα Kinase Activation, Leading to Potentiation of Apoptosis Induced by Cytokine and Chemotherapeutic Agents

Sandur

Ichikawa

Sethi

et al. 2006

Journal of Biological Chemistry

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310

260

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Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-B, suggesting plumbagin might affect the NF-B activation pathway. We found that plumbagin inhibited NF-B activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H 2 O 2 , cigarette smoke condensate, interleukin-1␤, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-B activation in certain tumor cells. The suppression of NF-B activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IB␣ kinase, IB␣ phosphorylation, IB␣ degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-B-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-␤, and the p65 subunit of NF-B. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-B-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-B activation pathway that leads to suppression of NF-B-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.

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Evidence That Receptor Activator of Nuclear Factor (NF)-κB Ligand Can Suppress Cell Proliferation and Induce Apoptosis through Activation of a NF-κB-independent and TRAF6-dependent Mechanism

Cited by 98 publications

References 77 publications

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

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

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Suppresses NF-κB Activation and NF-κB-regulated Gene Products Through Modulation of p65 and IκBα Kinase Activation, Leading to Potentiation of Apoptosis Induced by Cytokine and Chemotherapeutic Agents

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