Dataset Information

IKK? and TBK1 in diffuse large B-cell lymphoma: A possible mechanism of action of an IKK?/TBK1 inhibitor to repress NF-?B and IL-10 signalling.

ABSTRACT: The IKK-related kinases, IKK? and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-?B signalling. We investigated the expression and function of IKK? and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKK? and TBK1 inhibitors. To understand the function of IKK? and TBK1 secreted factors were determined following administration of inhibitors. Gene expression microarrays were used to determine the transcriptional effects of inhibitors. Higher TBK1 mRNA levels associated with poorer clinical outcome but IKK? and TBK1 were expressed in both germinal centre and non-germinal centre types of DLBCL. Survival of cell lines Ly10, Ly03 and Pfeiffer, and of some primary human lymphoma cells, was suppressed by a small molecule IKK?/TBK1 inhibitor, DMX3433. DMX3433 reduced IL-10 production from Ly10 and repressed NF-?B mediated transcription. Inhibition of IKK? and TBK1 warrants further investigation as a potential therapeutic route to suppress NF-?B signalling in lymphoma.

SUBMITTER: Carr M

PROVIDER: S-EPMC7576278 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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IKKε and TBK1 in diffuse large B-cell lymphoma: A possible mechanism of action of an IKKε/TBK1 inhibitor to repress NF-κB and IL-10 signalling.

Carr Matthew M Mamand Sami S Chapman Kathryn L KL Perrior Trevor T Wagner Simon D SD

Journal of cellular and molecular medicine 20200828 19

The IKK-related kinases, IKKε and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-κB signalling. We investigated the expression and function of IKKε and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKKε and TBK1 inhibitors. To understand the function of IKKε and TBK1 secreted factors were determined following administr ...[more]

PMID: 32858764

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Project description:Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-?/ TBK1/ NF-?B signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-?/TBK1 inhibitors and rescued by reconstitution of dominant active NF-?B. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-?/TBK1/NF-?B signaling axis.

Dataset Information

IKK? and TBK1 in diffuse large B-cell lymphoma: A possible mechanism of action of an IKK?/TBK1 inhibitor to repress NF-?B and IL-10 signalling.

Publications

IKKε and TBK1 in diffuse large B-cell lymphoma: A possible mechanism of action of an IKKε/TBK1 inhibitor to repress NF-κB and IL-10 signalling.

Similar Datasets

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