Regulation of CXCR4 gene expression in breast cancer cells under diverse stress conditions

Andreou, Kleopatra; Rajendran, Ramkumar; Krstic‐Demonacos, Marija; Demonacos, Constantinos

doi:10.3892/ijo.2012.1643

Cited by 12 publications

(9 citation statements)

References 40 publications

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“…This finding is quite unexpected since HIF-1α binds to hypoxia response elements (HREs) that exist in the promoters for several cytokines and chemokines important in the myeloid response to H. capsulatum including TNF-α, CCL2, and IL-10 (71–73). The loss of HIF-1α did not reduce pro-inflammatory cytokine production or cell recruitment to the lungs following infection.…”

Section: Discussionmentioning

confidence: 99%

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Fecher

Horwath

Friedrich

et al. 2016

The Journal of Immunology

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Hypoxia inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum since granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. Here we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to seven days post-infection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum. The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕ) constituted the majority of IL-10 producing cells. Deletion of HIF-1α in neutrophils or DCs did not alter fungal burden thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕ following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum. IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕ by IFN-γ and effective handling of H. capsulatum.

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Section: Discussionmentioning

confidence: 99%

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Fecher

Horwath

Friedrich

et al. 2016

The Journal of Immunology

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“…Transient transfections were carried out using the polyfect transfection reagent (Qiagen, Crawley, UK), according to the manufacturer’s instructions. Constructs used for ectopic expression included PCDNA3 [22,23], and β-galactosidase [22,23]. Human CYP2E1 luciferase reporter containing putative p53 binding sites was constructed by amplifying the upstream region of the CYP2E1 promoter -7873 to -5896 (counted from the translation initiation site) and inserting it in the pGL3 promoter luciferase vector (Promega, Madison, WI, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The process for chromatin immunoprecipitation (ChIP) has been described in the past [22,23]. Briefly chromatin was cross-linked with 1.42% formaldehyde and cross-linking was quenched by addition of 125 mM glycine.…”

Section: Methodsmentioning

confidence: 99%

Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells

et al. 2013

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IntroductionThe cytochrome P450 (CYP) enzymes are a class of heme-containing enzymes involved in phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 metabolises many xenobiotics and pro-carcinogens, it is not just expressed in the liver but also in many other tissues such as the kidney, the lung, the brain, the gastrointestinal tract and the breast tissue. It is induced in several pathological conditions including cancer, obesity, and type II diabetes implying that this enzyme is implicated in other biological processes beyond its role in phase I metabolism. Despite the detailed description of the role of CYP2E1 in the liver, its functions in other tissues have not been extensively studied. In this study, we investigated the functional significance of CYP2E1 in breast carcinogenesis.MethodsCellular levels of reactive oxygen species (ROS) were measured by H2DCFDA (2 2.9.2 2′,7′-dichlorodihydrofluorescein diacetate) staining and autophagy was assessed by tracing the cellular levels of autophagy markers using western blot assays. The endoplasmic reticulum stress and the unfolded protein response (UPR) were detected by luciferase assays reflecting the splicing of mRNA encoding the X-box binding protein 1 (XBP1) transcription factor and cell migration was evaluated using the scratch wound assay. Gene expression was recorded with standard transcription assays including luciferase reporter and chromatin immunoprecipitation.ResultsEctopic expression of CYP2E1 induced ROS generation, affected autophagy, stimulated endoplasmic reticulum stress and inhibited migration in breast cancer cells with different metastatic potential and p53 status. Furthermore, evidence is presented indicating that CYP2E1 gene expression is under the transcriptional control of the p53 tumor suppressor.ConclusionsThese results support the notion that CYP2E1 exerts an important role in mammary carcinogenesis, provide a potential link between ethanol metabolism and breast cancer and suggest that progression, and metastasis, of advanced stages of breast cancer can be modulated by induction of CYP2E1 activity.

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“…For instance, the cytokine Oncostatin M, belonging to the Interleukin-6 (IL-6) family of cytokines, enhances HIF-1α protein stability and induces HIF-1α de novo synthesis via activation of mTORC2 in breast Tumor Associated macrophages (TAMs), leading to inflammatory reprograming [ 144 ]. Worthy, CAFs isolated from breast tumor carcinomas promote angiogenesis by recruiting endothelial progenitor cells through stromal cell-derived factor 1 (SDF-1)/CXCR4 pathway [ 145 ], which is known to be activated by HIF-1α in several stressful conditions [ 146 ]. Likewise, cytokines as TGF-β and IL-1β may be released by breast cancer cells in a HIF-1α dependent manner and promote the conversion of normal fibroblasts to CAFs, hence encouraging tumor growth, metastatic spread, and neoangiogenesis [ 147 ].…”

Section: Hypoxia-inducible Hif-1α In Breast Cancer Cells and Cafsmentioning

confidence: 99%

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

Francesco

Maggiolini

Musti

2018

IJMS

119

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The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.

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Regulation of CXCR4 gene expression in breast cancer cells under diverse stress conditions

Cited by 12 publications

References 40 publications

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum

Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells

Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT

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