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The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target.

ABSTRACT: NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits.

SUBMITTER: Verzella D

PROVIDER: S-EPMC9496094 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target.

Verzella Daniela D Cornice Jessica J Arboretto Paola P Vecchiotti Davide D Di Vito Nolfi Mauro M Capece Daria D Zazzeroni Francesca F Franzoso Guido G

Biomedicines 20220908 9

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of ...[more]

PMID: 36140335

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Project description:An NF-κB target gene array (Panomics, Inc., Redwood City, CA) was performed to profile the PAO1-dependent expression pattern of 111 NF-kB-regulated genes in primary human airway epithelial cells (HAECs). A small scale microarray was carried out using NF-κB target gene array kit (Panomics, Inc., Redwood City, CA). A long sense-strand oligonucleotide for each of the 111 human genes that have been previously shown to be regulated by NF-KB signaling pathway was spotted in duplicate on the nitrocellulose membrane. Biotinylated DNA was spotted along the right and bottom sides of the array membrane as control. The arrays were performed according to the manufacturer’s instructions. In brief, HAECs were stimulated for 18 hours with the heat-killed bacteria PAO1 (multiplicity of infection: 100:1). Control experiment used PBS instead of bacteria. mRNA of HAECs was isolated using biotin-labeled oligo(dT)20 and streptavidin-conjugated magnetic particles (Roche, Germany). 500 ng mRNA was used to prepare biotin-labeled cDNA probes through incorporation of biotin-dUTP into cDNA via reverse transcription reactions. Each biotin-labeled cDNA probe was hybridized to an array membrane at 42°C overnight in a hybridization incubator (Fisher Scientific, Pittsburgh, PA). The membrane was washed and subjected to further incubations with blocking buffer and subsequent streptavidin-conjugated HRP. The membrane was developed through chemiluminescence reactions and detected immediately by 1 min exposure to Hyperfilm ECL X-ray films (Amersham, Piscataway, NJ). The dots on the array were quantified through densitometric analysis using GeneTools (Syngene, Frederick, MD) and the value of each dot was determined as D = (signal value – background value)/mean value of biotinylated DNA dots. Ratio (Dbacteria: Dcontrol) was used to determine the effect of bacteria stimulation on the gene regulation. Ratio>1 indicated an up-regulation of the gene. The experiments include two samples, one PBS control sample and one PAO1-stimulated sample.

Project description:ObjectiveTo determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes.MethodsMeta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC.ResultsA highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an 'interferon signature' may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis.ConclusionsThese findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently-incurable malignancy.

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The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target.

Publications

The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target.

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