The effects of IKK-beta inhibition on early NF-kappa-B activation and transcription of downstream genes

Bloom, Meghan J.; Saksena, Sachit D.; Swain, George P.; Behar, Marcelo; Yankeelov, Thomas E.; Sorace, Anna G.

doi:10.1016/j.cellsig.2018.12.004

Cited by 33 publications

(12 citation statements)

References 35 publications

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“…In previous research, SA exerted anti-tumor effects in various tumor cells via the NF-κB, JAK/STAT, and MAPK/iNOS pathways[11]. IKK complex is a core kinase which consists of IKKα, β, and γ subunits and mediates the phosphorylation of p65, which induces the activation of the NF-κB signaling pathway[12]. SA counteracts NF-κB activation by inhibiting activation of IKK through blocking ubiquitination of IKK-γ[13].…”

Section: Discussionmentioning

confidence: 99%

CARMA3/NF-κB signaling contributes to tumorigenesis of hepatocellular carcinoma and is inhibited by sodium aescinate

Hou

Li²,

Cui

et al. 2019

WJG

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BACKGROUNDPrimary hepatocellular carcinoma (HCC) is a very malignant tumor in the world. CARMA3 plays an oncogenic role in the pathogenesis of various tumors. However, the function of CARMA3 in HCC has not been fully clarified.AIMTo study the biological function of CAEMA3 in HCC.METHODSTissue microarray slides including tissues form 100 HCC patients were applied to access the expression of CARMA3 in HCC and its clinical relevance. Knockdown and overexpression of CARMA3 were conducted with plasmid transfection. MTT, colony formation, and apoptosis assays were performed to check the biological activity of cells.RESULTSHigher expression of CARMA3 in HCC was relevant to poor prognostic survival (P < 0.05). Down-regulation of CARMA3 inhibited proliferation and colony formation and induced apoptosis in HCC cell lines, while increasing its expression promoted tumorigenesis. We also found that sodium aescinate (SA), a natural herb extract, exerted anti-proliferation effects in HCC cells by suppressing the CARMA3/nuclear factor kappa-B (NF-κB) pathway.CONCLUSIONOverexpression of CARMA3 in HCC tissues correlates with a poor prognosis in HCC patients. CARMA3 acts pro-tumorigenic effects partly through activation of CARMA3/NF-κB. SA inhibits HCC growth by targeting CARMA3/NF-κB.

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Section: Discussionmentioning

confidence: 99%

CARMA3/NF-κB signaling contributes to tumorigenesis of hepatocellular carcinoma and is inhibited by sodium aescinate

Hou

Li²,

Cui

et al. 2019

WJG

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“…6A). Due to its known effect on IL-1 transcription (32,33), we focused on CD11b-agonist regulation of NFκB. First, we found that GB1275 lost its ability to decrease IL-1 expression further when NFκB p65 was silenced by siRNA (Sup Fig.…”

Section: Nfκb/il-1 Signaling In Tams Is Downregulated By Agonism Of C...mentioning

confidence: 99%

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Liu

Hogg

Zuo

et al. 2022

Preprint

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Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

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“…A variety of extracellular signals, stimulating various receptor types, result in the activation of the IκB kinase (IKK). IKK, in turn, phosphorylates the IκBα protein, which results in its dissociation from NF-κB dimers and eventual proteasomal degradation, allowing activated NF-κB to translocate into the nucleus and bind to the promoters of multiple target genes [188].…”

Section: The Nf-κb Pathwaymentioning

confidence: 99%

A Signaling View into the Inflammatory Tumor Microenvironment

Pereira

Jordan

Matos

2021

Immuno

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The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.

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The effects of IKK-beta inhibition on early NF-kappa-B activation and transcription of downstream genes

Cited by 33 publications

References 35 publications

CARMA3/NF-κB signaling contributes to tumorigenesis of hepatocellular carcinoma and is inhibited by sodium aescinate

CARMA3/NF-κB signaling contributes to tumorigenesis of hepatocellular carcinoma and is inhibited by sodium aescinate

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

A Signaling View into the Inflammatory Tumor Microenvironment

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