Modification of Cysteine 179 of IκBα Kinase by Nimbolide Leads to Down-regulation of NF-κB-regulated Cell Survival and Proliferative Proteins and Sensitization of Tumor Cells to Chemotherapeutic Agents

Gupta, Subash C.; Prasad, Sahdeo; Reuter, Simone; Kannappan, Ramaswamy; Yadav, Vivek R.; Ravindran, Jayaraj; Hema, Padmanabhan S.; Chaturvedi, Madan M.; Nair, Mangalam S.; Aggarwal, Bharat B.

doi:10.1074/jbc.m110.161984

Cited by 102 publications

(109 citation statements)

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“…Nimbolide (33), butein (43), 3-formylchromone (44), and other compounds have been reported to exhibit similar effects on Cys 179 . In addition, we found that piperlongumine also blocked the phosphorylation of serine 181 and tyrosine 188 in IKKb induced by TNFa.…”

Section: Discussionmentioning

confidence: 99%

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Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

Han

Gupta

Prasad

et al. 2014

Molecular Cancer Therapeutics

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Recently, two different reports appeared in prominent journals suggesting a mechanism by which piperlongumine, a pyridine alkaloid, mediates anticancer effects. In the current report, we describe another novel mechanism by which this alkaloid mediates its anticancer effects. We found that piperlongumine blocked NF-kB activated by TNFa and various other cancer promoters. This downregulation was accompanied by inhibition of phosphorylation and degradation of IkBa. Further investigation revealed that this pyridine alkaloid directly interacts with IkBa kinase (IKK) and inhibits its activity. Inhibition of IKK occurred through interaction with its cysteine 179 as the mutation of this residue to alanine abolished the activity of piperlongumine. Inhibition in NF-kB activity downregulated the expression of proteins involved in cell survival (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, survivin), proliferation (c-Myc, cyclin D1), inflammation (COX-2, IL6), and invasion (ICAM-1, -9, CXCR-4, VEGF). Overall, our results reveal a novel mechanism by which piperlongumine can exhibit antitumor activity through downmodulation of proinflammatory pathway. Mol Cancer Ther; 13(10); 2422-35. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

“…These results suggested that inhibition of NF-kB activation by piperlongumine does not suppress DNA binding directly. This compound may, however, use the inhibitory mechanism of nimbolide (33) and g-tocotrienol (34), which inhibit NF-kB activation indirectly.…”

Section: Piperlongumine Does Not Directly Affect the Binding Of Nf-kbmentioning

confidence: 99%

Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

Han

Gupta

Prasad

et al. 2014

Molecular Cancer Therapeutics

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“…Electrophoretic Mobility Shift Assay. To examine NF-B activation in leukemia and myeloma cells, nuclear extracts were prepared and an EMSA was performed using these extracts (Gupta et al, 2010c). The EMSAs for AP-1 and Oct-1 were performed as described for NF-B using 32 P end-labeled doublestranded oligonucleotides.…”

Section: Methodsmentioning

confidence: 99%

“…To determine the effect of bharangin on TNF-␣-induced invasion, the BD BioCoat tumor invasion system (BD Biosciences, San Jose, CA) was used employing a method as described previously (Gupta et al, 2010c).…”

Section: Methodsmentioning

confidence: 99%

Bharangin, a Diterpenoid Quinonemethide, Abolishes Constitutive and Inducible Nuclear Factor-κB (NF-κB) Activation by Modifying p65 on Cysteine 38 Residue and Reducing Inhibitor of Nuclear Factor-κB α Kinase Activation, Leading to Suppression of NF-κB-Regulated Gene Expression and Sensitization of Tumor Cells to Chemotherapeutic Agents

et al. 2011

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Although inflammatory pathways have been linked with various chronic diseases including cancer, identification of an agent that can suppress these pathways has therapeutic potential. Herein we describe the identification of a novel compound bharangin, a diterpenoid quinonemethide that can suppress pro-inflammatory pathways specifically. We found that bharangin suppresses nuclear factor (NF)-B activation induced by pro-inflammatory cytokine, tumor promoter, cigarette smoke, and endotoxin. Inhibition of NF-B activation was mediated through the suppression of phosphorylation and degradation of inhibitor of nuclear factor-B (IB␣); inhibition of IB␣ kinase activation; and suppression of p65 nuclear translocation, and phosphorylation. The diterpenoid inhibited binding of p65 to DNA. A reducing agent reversed the inhibitory effect, and mutation of the Cys 38 of p65 to serine abrogated the effect of bharangin on p65-DNA binding. Molecular docking revealed strong interaction of the ligand with the p65 via two hydrogen bonds one with Lys 37 (2.204 Å) and another with Cys 38 (2.023 Å). The inhibitory effect of bharangin on NF-B activation was specific, inasmuch as binding of activator protein-1 and octameric transcription factor 1 to DNA was not affected. Suppression of NF-B activation by this diterpenoid caused the downregulation of the expression of proteins involved in tumor cell survival, proliferation, invasion, and angiogenesis, leading to potentiation of apoptosis, suppression of proliferation, and invasion of tumor cells. Furthermore, the genetic deletion of p65 and mutation of p65Cys 38 residue to Ser abolished the affect of bharangin. Overall, our results demonstrate that bharangin specifically inhibits the NF-B activation pathway by modifying p65 and inhibiting IB␣ kinase activation and potentiates apoptosis in tumor cells.

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“…In addition, resveratrol was found to inhibit proliferation and induce apoptosis in several human tumor cells (7,8). It has been previously reported that resveratrol can inhibit the growth of malignant B-cell lines in a dose-and timedependent manner (9,10). However, EBV infection might confer additional survival potential to malignant B cells, also depending on the different programs of latent gene expression adopted by the virus.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program

Leo

Arena

Stecca

et al. 2011

Molecular Cancer Research

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Resveratrol (3,4 0 ,5-trihydroxy-trans-stilbene), a polyphenolic natural product, shows chemopreventive properties against several cancers, heart diseases, inflammation, and viral infections. Epstein Barr virus (EBV), a g-herpesvirus, contributes to the development of several human cancers including Burkitt's lymphoma (BL). In this study, we asked whether treatment with resveratrol would affect the viability of EBV-positive BL cells displaying different forms of latency. We report here that resveratrol, regardless of EBV status, induces caspasedependent apoptosis by arresting cell-cycle progression in G 1 phase. However, resveratrol strongly induced apoptosis in EBV(À) and latency I EBV(þ) cells, whereas latency II and latency III EBV(þ) BL cells showed a survival advantage that increased with the extent of the pattern of viral gene expression. Resveratrol-induced cellcycle arrest and apoptosis occurred in association with induction of p38 MAPK phosphorylation and suppression of ERK1/2 signaling pathway. Moreover, NF-kB DNA-binding activity was inhibited in all BL lines except EBV (þ) latency III cells.LMP1 oncogene, which is expressed in latency III phenotype, is involved with the higher resistance to the antiproliferative effect of resveratrol because siRNA-mediated inhibition of LMP1 greatly increased the sensitivity of latency III BL cells as well as that of lymphoblastoid cell lines to the polyphenol. We propose that a combined resveratrol/siRNA strategy may be a novel approach for the treatment of EBV-associated B-cell malignancies in which the viral pattern of gene expression has been defined. Mol Cancer Res; 9(10); 1346-55. Ó2011 AACR.

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Modification of Cysteine 179 of IκBα Kinase by Nimbolide Leads to Down-regulation of NF-κB-regulated Cell Survival and Proliferative Proteins and Sensitization of Tumor Cells to Chemotherapeutic Agents

Cited by 102 publications

References 45 publications

Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB–Regulated Gene Products

Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program

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