The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NFκB Transcription Factors

Rauert-Wunderlich, Hilka; Siegmund, Daniela; Maier, Eduard; Giner, Tina; Bargou, Ralf C.; Wajant, Harald; Stühmer, Thorsten

doi:10.1371/journal.pone.0059292

Cited by 58 publications

(48 citation statements)

References 28 publications

(32 reference statements)

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“…It has previously been demonstrated that BAY 11-7082 is toxic to multiple myeloma cells independent of its known effects on the NF-κB pathway, indicating off-target effects 40 . This study did not, however, take into account the more recent report of the inhibition of protein tyrosine phosphatases by this compound 39 .…”

Section: Resultsmentioning

confidence: 99%

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Hodge

Markin

et al. 2015

ACS Chem. Biol.

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Ubc13 is an E2 ubiquitin conjugating enzyme that functions in nuclear DNA damage signaling and cytoplasmic NF-κB signaling. Here we present the structures of complexes of Ubc13 with two inhibitors, NSC697923 and BAY 11-7082, which inhibit DNA damage and NF-κB signaling in human cells. NSC697923 and BAY 11-7082 both inhibit Ubc13 by covalent adduct formation through a Michael addition at the Ubc13 active site cysteine. The resulting adducts of both compounds exploit a binding groove unique to Ubc13. We developed a Ubc13 mutant which resists NSC697923 inhibition and, using this mutant, we show that the inhibition of cellular DNA damage and NF-κB signaling by NSC697923 is largely due to specific Ubc13 inhibition. We propose that unique structural features near the Ubc13 active site could provide a basis for the rational development and design of specific Ubc13 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Hodge

Markin

et al. 2015

ACS Chem. Biol.

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“…Blocking of TAK-1 [56] decreased MPLA-, PPC- and SIN-1-induced SEAP release, which suggests decreased AP-1 and NF-κB activation. U0126, MEK inhibitor in AP-1 signaling pathway [57], weakly inhibited TLR4 agonist- and prooxidant-induced SEAP release, whereas Bay 11-7082, an IKK inhibitor [58], completely abolished it [32]. This indicates that NF-κB activation may be a more dominant event downstream of the TLR4 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Activation of c-Src: A hub for exogenous pro-oxidant-mediated activation of Toll-like receptor 4 signaling

Karki

Zhang

Igwe

2014

Free Radical Biology and Medicine

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Summary To study the role of c-Src kinase in prooxidant-induced stimulation of TLR4, we used LPS-EK and MPLA as TLR4 specific agonists and positive controls, and SIN-1 and PPC as prooxidant sources. We used HEK-Blue mTLR4 cell line that is stably transfected with mouse TLR4 and that expresses optimized SEAP reporter under the control of a promoter inducible by NF-κB transcription factor. The level of SEAP released due to TLR4 stimulation was a measure of NF-κB activation. Treatment with either the prooxidants or LPS-EK increased SEAP release and TNF-α production in these cells. These treatments also increased intracellular ROS accumulation with an enhanced production of nitric oxide and TBARS to confirm oxidant stress in these cells. Pretreatment with c-Src kinase inhibitors, PP2 and CA-pY, which act by different mechanisms, decreased these parameters. Pretreatment with SSG, a c-Src activator, enhanced the effects promoted by LPS-EK and prooxidants, and rescued cells from PP2- and Ca-pY-induced effects. Curiously, prooxidants but not TLR4 agonist increased the ratio of TNFα to IL-10 released suggesting that prooxidants can initiate and maintain an imbalance of TNFα production over IL-10. To different degrees, both prooxidant and TLR4 agonist increased formation of c-Src complexes with TLR4 and IκB-α as coimmunoprecipitates. Both prooxidant and TLR4 agonist increased c-Src phosphorylation of Tyr-42 residue in IκB-α, but prooxidant-induced effect was more robust and much longer lasting. Taken together, these studies provide a mechanism whereby c-Src assumes a central role in prooxidant-induced NF-κB activation in TLR4 signaling. Prooxidant-induced activation of TLR4 through c-Src/NFκB/IκB-α coupling provides a basis for a molecular dissection of the initiation and maintenance of sterile inflammation that may serve as a “pathophysiologic primer” for many diseases.

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“…One of the most important phosphorylation sites in NF-kBp65 activation is Ser 536 (17). Interestingly, the NF-kB inhibitor BAY11-7082 inhibits the IkB kinase (42), which phosphorylates NF-kBp65 exactly at this Ser 536 position (18,43). Because BAY11-7082 decreased IL-10 production in SCRIPT-KD-DCs ( Fig.…”

Section: Dc-script Knockdown Leads To More S536 Phosphorylation Of Nfmentioning

confidence: 91%

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Søndergaard

Poghosyan

Hontelez

et al. 2015

The Journal of Immunology

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The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.

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The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NFκB Transcription Factors

Cited by 58 publications

References 28 publications

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting

Activation of c-Src: A hub for exogenous pro-oxidant-mediated activation of Toll-like receptor 4 signaling

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

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