The breast cancer cells response to chronic hypoxia involves the opposite regulation of NF-kB and estrogen receptor signaling

Scherbakov, Alexander M.; Lobanova, Yulia S.; Shatskaya, V. A.; Красильников, М. А.

doi:10.1016/j.steroids.2009.02.003

Cited by 14 publications

(8 citation statements)

References 34 publications

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“…Intriguingly, previous studies have already shown that ZAS3 [17, 34] and E2 [35] both target NFκB and lead to functional repression, just as observed in SLE [36]. Therefore, we speculate that E2-mediated ZAS3 overexpression could contribute to NFκB inhibition in PBMCs of SLE patients.…”

Section: Discussionsupporting

confidence: 53%

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

Young

Friedman

Kaffenberger

et al. 2013

Molecular Immunology

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Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and β into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ERα binding to putative EREs within the ZAS3 gene and ERα knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFNα has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.

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Section: Discussionsupporting

confidence: 53%

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

Young

Friedman

Kaffenberger

et al. 2013

Molecular Immunology

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“…New to science, our studies demonstrated that EF24 profoundly conferred IR-induced cell killing, survival signaling and more importantly, the results depict that EF24 targets IR-induced NFκB for this causal effect. To that note, studies have shown that, EF24 has potent anti-proliferative activity against a number of cancer cell lines including colon [21], breast [22], and ovarian [23]. Synthetic chemical analogues to molecularly targeted chemotherapeutic drugs and chemopreventive photochemical confound a myriad of molecular events in host and tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

“…To that end, a synthetic analog of curcumin, EF24 (3,5-Bis(2-flurobenzylidene) piperidin-4-one), with better pharmacokinetic and improved physiochemical properties has been well tolerated in animal models [19,20]. EF24 has been shown to possess anti-tumorigenic [21–23] activity and has been demonstrated to directly inhibit IKKβ, a probable explanation for the improved therapeutic potency over curcumin [24]. We recently have shown that EF24 suppresses NFκB dependent inflammation in dendritic cells [25].…”

Section: Introductionmentioning

confidence: 99%

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

et al. 2013

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Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK–PN–DW, MC-IXC and SK–N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.

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“…All of these alterations will finally lead to angiogenesis, matrix degradation and metastasis in cancer. Cancer cells adapt to hypoxia for survival [26]. …”

Section: Discussionmentioning

confidence: 99%

BlyS is up-regulated by hypoxia and promotes migration of human breast cancer cells

Zhu

Sun

Lin

et al. 2012

J Exp Clin Cancer Res

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BackgroundThe role of B Lymphocyte Stimulator (BLyS) in the survival of malignant B cells and the maintenance of normal B cell development and homeostasis has been intensively studied in the literature. However, the influence of BLyS on breast cancer progression remains unclear. The study aimed to investigate the effect of hypoxia on BLyS regulation, cell migratory response to BLyS and the possible molecular mechanisms.MethodsIn this study, we examined the role of BLyS in the migration of human breast cancer cells by transwell assay. We also explored whether BLyS and its receptors expressed in human breast cancer cell lines by immunofluorescence and Western Blotting. Then we detected the expression level of BLyS in both normoxic and hypoxic conditions by real time-PCR and Western Blotting. Pathways involved were confirmed by Western Blotting, immunofluorescence, transwell assay and luciferase assay.ResultsAccording to our study, the expression level of BlyS was increased in human breast cancer cell lines in hypoxic conditions. Up-regulation of this protein led to activation and nuclear translocation of NF-kappa B p65. We also found that the number of migrated cells was increased in the presence of BLyS and inhibition of phosphorylation of Akt attenuated the enhanced migratory response.ConclusionsIt suggested that better understanding of BLyS, an immunopotentiator, may offer a potential therapeutic target for the treatment of human breast cancers. In addition, BLyS promoted breast cancer cells migration, underscoring the necessity of appropriate applications of immunopotentiators to cancer treatment.

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The breast cancer cells response to chronic hypoxia involves the opposite regulation of NF-kB and estrogen receptor signaling

Cited by 14 publications

References 34 publications

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus

Novel Synthetic Monoketone Transmute Radiation-Triggered NFκB-Dependent TNFα Cross-Signaling Feedback Maintained NFκB and Favors Neuroblastoma Regression

BlyS is up-regulated by hypoxia and promotes migration of human breast cancer cells

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