3-Phosphoinositide-dependent Protein Kinase-1-mediated IκB Kinase β (IKKB) Phosphorylation Activates NF-κB Signaling

Tanaka, Hiroshi; Fujita, Naoya; Tsuruo, Takashi

doi:10.1074/jbc.m506235200

Cited by 90 publications

(62 citation statements)

References 46 publications

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“…We found that TQ is not a direct inhibitor of IKK (data not shown). Several kinases, such as MAPK kinase kinase 1 (58), MAPK kinase kinase 3 (59), PKC (60); glycogen synthase kinase-3h (61), TAK1 (62), PDK1 (63), and Akt (64), have all been reported to function upstream of IKK. Recent studies, however, indicate that TAK1 plays a major role in TNF-induced NF-nB activation through its interaction with TAB1 and TAB2.…”

Section: Discussionmentioning

confidence: 99%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

296

218

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Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-KB (NF-KB) signaling, we investigated in detail the effect of this quinone on NF-KB pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor -induced NF-KB activation in a dose-and time-dependent manner and inhibited NF-KB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-KB activation correlated with sequential inhibition of the activation of IKBA kinase, IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-KB -dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-KB -regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-KB activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.

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Section: Discussionmentioning

confidence: 99%

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Sethi

Ahn

Aggarwal

2008

Molecular Cancer Research

296

218

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“…Furthermore, PDK1-mediated activation of NF-kB signaling pathways was shown to occur through direct IKKB phosphorylation independently to AKT signaling pathways. 31 In such context, the relationship between p53 and PI3K and between PTEN and PI3K demonstrated here that inhibition of PI3K could avoid the 'cross-talk' between PI3K downstream signaling pathways such as AKT and IKK/NF-kB signaling pathways. These data further suggest that PI3K could be a promising and attractive target for cancer therapy in patients harboring PTEN and/or P53 mutations with upregulation AKT signaling pathways.…”

Section: Discussionmentioning

confidence: 83%

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

Bouali

Ramacci

et al. 2009

Cancer Gene Ther

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Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody whose activity is related to the inhibition of EGFR downstream signaling pathways. P53 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) have been reported to control the functionality of PI3K/AKT signaling. In this study we evaluated whether reintroducing P53 using non-viral gene transfer enhances PTEN-mediated inhibition of PI3K/AKT signaling by cetuximab in PC3 prostate adenocarcinoma cell line bearing p53 and pten mutations. Signaling phosphoproteins expression was analyzed using Bio-Plex phosphoprotein array and western blot. Apoptosis induction was evaluated from BAX expression, caspase-3 activation and DNA fragmentation analyses. The results presented show that p53 and pten gene transfer additionally mediated cell growth inhibition and apoptosis induction by restoral of signaling functionality, which enabled the control of PI3K/AKT and MAPKinase signaling pathways by cetuximab in PC3 cells. These results highlight the interest of the analysis of signaling phosphoproteins expression as molecular predictive markers for response to cetuximab and show that p53 and pten mutations could be key determinants of cell response to cetuximab through the functional impact of these mutations on cell signaling.

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“…We also investigated how celastrol suppresses IKK activation. Several kinases, such as MEKK1, 54 MEKK3, 55 PKC, 56 glycogen synthase kinase-3␤, 57 TAK1, 52 PDK1, 58 and Akt 59 have been reported to function upstream of IKK. Recent studies, however, indicate that TAK1 plays a major role in the canonical pathway activated by cytokines through its interaction with TAB1 and TAB2.…”

Section: Discussionmentioning

confidence: 99%

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

Sethi

Ahn

Pandey

et al. 2006

Blood

305

242

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Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-B activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-X L , c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-B, we postulated that celastrol mediates its effects by modulating the NF-B pathway. We found that celastrol suppressed both inducible and constitutive NF-B activation. Celastrol was found to inhibit the TNF-induced activation of I B␣ kinase, I B␣ phosphorylation, I B␣ degradation, p65 nuclear trans- IntroductionModern targeted therapies for most chronic illnesses, including cancer, have been mostly unsuccessful because of their ineffectiveness, lack of safety, and cost. Although monotherapy was advocated at one time, recent experience indicates that agents that target multiple pathways have more potential in cancer treatment. This understanding has led to combination therapy. Although traditional therapies have been around for thousands of years, their active components and their mechanisms of action remain undefined. Identification of an active chemical entity and its molecular targets can lead to rediscovery of the clinical potential of such therapies, as in the case of paclitaxel, derived from Taxus (yew) species during a random screening of US Department of Agriculture collection of plants. 1 Celastrol, also known as tripterine, is one such compound that was originally identified from traditional Chinese medicine ("God of Thunder Vine") almost 3 decades ago and used for the treatment of cancer and other inflammatory diseases. 2 Celastrol, a triterpenoid from the Celastracae family and extracted from the plant Tripterygium wilfordii, 3 has attracted interest, especially for its potential anti-inflammatory effects. 4 The in vivo anti-inflammatory effects of this triterpene have been demonstrated in animal models of collagen-induced arthritis, 5 Alzheimer disease, 6 asthma, 7 systemic lupus erythematosus, 8,9 and rheumatoid arthritis. 10 Celastrol is also known to inhibit the proliferation of a variety of tumor cells, including those from leukemia, 11 gliomas, 12 and prostate cancer. 13 The ability of celastrol to modulate the expression of proinflammatory cytokines, 3,14,15 6 inducible nitric oxide (NO) synthase (iNOS), 16 adhesion molecules in endothelial cells, 17 proteasome activity, 13 topoisomerase II, 11 potassium channels, 18 and heat shock response 19 has been reported. However, the molecular mechanism underlying the ...

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3-Phosphoinositide-dependent Protein Kinase-1-mediated IκB Kinase β (IKKB) Phosphorylation Activates NF-κB Signaling

Cited by 90 publications

References 46 publications

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation

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