Regulation of Inflammation by the NF-κB Pathway in Ovarian Cancer Stem Cells

Article (PDF Available)inAmerican Journal Of Reproductive Immunology 65(4):438-47 · April 2011with34 Reads
DOI: 10.1111/j.1600-0897.2010.00914.x · Source: PubMed
The NFκB pathway is a major source of pro-inflammatory cytokines, which may contribute to cancer chemoresistance. We showed that constitutive NFκB activity is characteristic of the ovarian cancer stem cells (OCSCs). The aim of this study is to determine whether the inhibition of NFκB by Eriocalyxin B (EriB) in the OCSCs may induce cell death in otherwise chemoresistant cells. OCSCs and mature ovarian cancer cells (mOCCs) were treated with increasing concentrations of EriB. Cell viability was measured using the Celltiter 96 assay, and caspase activity was quantified using Caspase-Glo™ assay. Cytokine levels were quantified using xMAP technology. EriB decreased the percent of viable cells in all cultures tested with GI(50) of 0.5-1 μm after 48 hrs of treatment. The intracellular changes associated with EriB-induced cell death are: (i) inhibition of NF-κB activity; (ii) decreased cytokine production; (iii) activation of caspases; and (iv) down-regulation of XIAP. In addition, EriB is able to sensitize OCSCs to TNFα and FasL-mediated cell death. Inhibition of the NFκB pathway induces cell death in the OCSCs. Because the OCSCs may represent the source of recurrence and chemoresistance, the use of NFκB inhibitors like EriB may prevent recurrence in patients with ovarian cancer.

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Available from: Gil Mor, Jan 19, 2015
    • "In addition to direct evidence of preferential NF-κB activation in CSC subsets of tumors, several groups have taken an unbiased approach of profiling gene expression and defining CSC-associated signatures. This has revealed an inflammatory signature, which can frequently be tightly associated with NF-κB regulation, in a variety of tumors such as glioblastoma, breast, prostate, and ovarian cancers [94][95][96][97][98][99]. Perhaps not surprisingly, some of the same oncoproteins previously mentioned to activate NFκB also participate in the CSC subpopulations of tumors. "
    [Show abstract] [Hide abstract] ABSTRACT: The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology.
    Full-text · Article · Apr 2016
    • "Either the dimerization or the cellular distribution of p50/p65 in our current study turned out to be not affected by the binding of EriB with p50, which is consistent with previous studies [4, 5]. It was also reported that EriB-mediated NF-κB inactivation of acute myeloid leukemia cells and the ovarian cancer stem cells was associated with the inhibition of nuclear translocation of NF-κB [2, 3]. We assumed that the difference could be due to the different types of cells tested and experimental conditions, such as the doses and time used for EriB treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: As an ent-kaurene diterpenoid isolated from Isodon eriocalyx var. Laxiflora, Eriocalyxin B (EriB) possesses potent bioactivity of antitumor and anti-autoimmune inflammation, which has been suggested to work through inhibition of NF-kappaB (NF-κB) signaling. However, the direct target of EriB remains elusive. In this study, we showed that EriB induced apoptosis is associated with the inhibition of NF-κB signaling in SMMC-7721 hepatocellular carcinoma cells. With activity-based probe profiling, we identified p50 protein as the direct target of EriB. We showed that cysteine 62 is the critical residue of p50 for EriB binding through the α, β-unsaturated ketones. As the result, EriB selectively blocks the binding between p50 and the response elements, whereas having no effect on the dimerization or the nuclear translocation of p50 and p65. SiRNA mediated knockdown of p50 attenuated the apoptosis induced by EriB in SMMC-7721 cells. Taken together, our studies illustrated that EriB induces cancer cell apoptosis through interfering with the binding between NF-κB and the response elements by targeting the cysteine 62 of p50, which highlights its potential for the development of p50 targeted cancer therapeutic agents.
    Full-text · Article · Oct 2014
    • "It is thought that CSCs are able to survive conventional chemotherapeutic treatments, which usually target fast-dividing cells and give rise to recurrent tumors that are more chemoresistant and more aggressive878889. Using CD44 as a marker, our group identified Epithelial Ovarian Cancer (EOC) stem cells based on their capacity to recreate the original tumor when injected into mice9091929394. We have fully characterized the molecular phenotype of these cells [90, 91, 95] and demonstrated their plasticity – they are able to differentiate and lose stemness markers in vitro and in vivo and, more importantly, are able to differentiate into endothelial cells [91, 96]. "
    [Show abstract] [Hide abstract] ABSTRACT: The transcription factor TWIST1 is a highly evolutionally conserved basic Helix-Loop-Helix (bHLH) transcription factor that functions as a master regulator of gastrulation and mesodermal development. Although TWIST1 was initially associated with embryo development, an increasing number of studies have shown TWIST1 role in the regulation of tissue homeostasis, primarily as a regulator of inflammation. More recently, TWIST1 has been found to be involved in the process of tumor metastasis through the regulation of Epithelial Mesenchymal Transition (EMT). The objective of this review is to examine the normal functions of TWIST1 and its role in tumor development, with a particular focus on ovarian cancer. We discuss the potential role of TWIST1 in the context of ovarian cancer stem cells and its influence in the process of tumor formation.
    Full-text · Article · Sep 2014
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