Inhibitors of NF-κB signaling: 785 and counting

Gilmore, Thomas D.; Herscovitch, Melanie

doi:10.1038/sj.onc.1209982

Cited by 546 publications

(515 citation statements)

References 165 publications

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“…NF-κB1 (p105/p50) and NF-κB2 (p100/p52) need to be processed to become active and translocate to the nucleus where they associate with RelA (p65), c-Rel and RelB in different hetero-and homodimers to form the transcriptionally active complex. 16 Mice deficient in RelB show reduced numbers of MZ B cells, 17 whereas mice lacking a negative regulator of NF-κB have more MZ B cells 18 similar to mice that lack the inhibitory p100 subunit of NF-κB2. 19 We therefore quantified the abundance of all NF-κB proteins in the cytosol and the nucleus by immunoblotting of subcellular fractions obtained from freshly isolated splenocytes.…”

Section: Resultsmentioning

confidence: 99%

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

et al. 2015

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The endoplasmic reticulum (ER) serves as the major intracellular Ca 2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca 2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca 2+ store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca 2+ levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca 2+ levels, suggesting an exhausted mitochondrial Ca 2+ buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca 2+ homeostasis in lymphocytes. Cell Death and Differentiation (2016) 23, 358-368; doi:10.1038/cdd.2015; published online 16 October 2015The endoplasmic reticulum (ER) serves as the major intracellular calcium (Ca 2+ ) store, the release of which controls a vast array of cellular functions from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. 1 Dysregulated release of ER Ca 2+ , in contrast, initiates programmed cell death by several mechanisms including mitochondrial Ca 2+ overload, depolarization, ATP loss and cytochrome c release. 2 Besides this, the ER also has a key role in the synthesis, folding and sorting of proteins destined for the secretory pathway. The deleterious consequences of an increase in unfolded proteins is called ER stress and can be antagonized by the unfolded protein response (UPR), a mechanism that coordinates a simultaneous increase in the ER folding capacity and a decrease in folding load. In the case of insufficient adaptation to ER stress, cells undergo apoptosis. 3 BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is an evolutionarily conserved protein that bridges both the Ca 2+ homeostasis and UPR functions of the ER. 4 BI-1 was first identified in a screen for human proteins capable of inhibiting BAX-mediated cell death in yeast. 5 In mammalian cells, BI-1's antiapoptotic function is most pronounced in paradigms of ER stress 6 and involves changes in the amount of Ca 2+ that can be released from intracellular stores. 6,7 BI-1 is a highly hydrophobic protein that forms a Ca 2+ pore responsible for its Ca 2+ leak properties 8 and is the founding member of a family of six proteins with similar properties. 9 The increase in the ER Ca 2+ lea...

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Section: Resultsmentioning

confidence: 99%

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

et al. 2015

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“…For instance, inhibition of NF-κB activity due to elevated Nfkbia expression across many tissue types appears to be a common response to CR. At least one proposed CR-mimetic compound, resveratrol, mimics this effect (Manna et al, 2000;Pendurthi et al, 2002;Iyori et al, 2008), and similar responses might also be attained by treatment with other NF-κB inhibitors now undergoing development (Gilmore and Herscovitch, 2006).…”

Section: Discussionmentioning

confidence: 95%

Genes regulated by caloric restriction have unique roles within transcriptional networks

Swindell

2008

Mechanisms of Ageing and Development

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Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.

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“…To our knowledge, none of the many NF-kB signaling inhibitors described so far (Gilmore and Herscovitch, 2006) have been shown in vivo to increase chemotherapy efficiency in CRC. Taken together, our results provide a rationale for using the IKK2 inhibitor AS602868 combined with CPT-11 as a promising therapeutic strategy for clinical testing in CPT-11 refractory CRC and probably other solid tumours.…”

Section: Discussionmentioning

confidence: 98%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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NF-kB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kB activation. In human colon cancer cells, inhibition of NF-kB using 10 mM AS602868 induced a 30 -50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg À1 AS602868 associated with 30 mg kg À1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFa on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours.

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Inhibitors of NF-κB signaling: 785 and counting

Cited by 546 publications

References 165 publications

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

Genes regulated by caloric restriction have unique roles within transcriptional networks

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

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