Glucocorticoid Receptor Expression and Antiproliferative Effect of Dexamethasone on Human Melanoma Cells

Dobos, Judit; Kenessey, István; Tı́már, József; Ladányi, Andrea

doi:10.1007/s12253-011-9377-8

Cited by 24 publications

(19 citation statements)

References 26 publications

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“…Human and murine melanoma cells express high-affinity glucocorticoid receptors (GCRs) [34]; and the presence of adrenoceptors (ARs) has been also detected in different melanoma cells [24]. Moreover, the presence of GCRs [35] and β ARs [36] in B16 melanoma cells has been reported.…”

Section: Resultsmentioning

confidence: 99%

“…Glucocorticoids (such as dexamethasone) are widely used in cancer therapy and may have cell type-specific pro- or antiapoptotic effects, although when applied at high therapeutic doses their anti-tumor effects prevail [34]. Nevertheless there are very limited data regarding possible direct effects of stress hormones, at in vivo pathophysiological levels, on cancer cell proliferation [49].…”

Section: Resultsmentioning

confidence: 99%

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Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism

et al. 2013

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BackgroundInterleukin (IL)-6 (mainly of tumor origin) activates glutathione (GSH) release from hepatocytes and its interorgan transport to B16-F10 melanoma metastatic foci. We studied if this capacity to overproduce IL-6 is regulated by cancer cell-independent mechanisms.MethodsMurine B16-F10 melanoma cells were cultured, transfected with red fluorescent protein, injected i.v. into syngenic C57BL/6J mice to generate lung and liver metastases, and isolated from metastatic foci using high-performance cell sorting. Stress hormones and IL-6 levels were measured by ELISA, and CRH expression in the brain by in situ hybridization. DNA binding activity of NF-κB, CREB, AP-1, and NF-IL-6 was measured using specific transcription factor assay kits. IL-6 expression was measured by RT-PCR, and silencing was achieved by transfection of anti-IL-6 small interfering RNA. GSH was determined by HPLC. Cell death analysis was distinguished using fluorescence microscopy, TUNEL labeling, and flow cytometry techniques. Statistical analyses were performed using Student’s t test.ResultsPlasma levels of stress-related hormones (adrenocorticotropin hormone, corticosterone, and noradrenaline) increased, following a circadian pattern and as compared to non-tumor controls, in mice bearing B16-F10 lung or liver metastases. Corticosterone and noradrenaline, at pathophysiological levels, increased expression and secretion of IL-6 in B16-F10 cells in vitro. Corticosterone- and noradrenaline-induced transcriptional up-regulation of IL-6 gene involves changes in the DNA binding activity of nuclear factor-κB, cAMP response element-binding protein, activator protein-1, and nuclear factor for IL-6. In vivo inoculation of B16-F10 cells transfected with anti-IL-6-siRNA, treatment with a glucocorticoid receptor blocker (RU-486) or with a β-adrenoceptor blocker (propranolol), increased hepatic GSH whereas decreased plasma IL-6 levels and metastatic growth. Corticosterone, but not NORA, also induced apoptotic cell death in metastatic cells with low GSH content.ConclusionsOur results describe an interorgan system where stress-related hormones, IL-6, and GSH coordinately regulate metastases growth.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism

et al. 2013

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“…Dexamethasone (Dex), a synthetic GCs, prevents the cell growth of many hematologic malignant cells and solid tumor cell types, including multiple myeloma (3), leukemia (4), prostate cancer (5), hepatoma (6), melanoma (7), osteosarcoma (8), lung cancer (9), breast cancer (10) and ovarian cancer cells (11). However, the biological effect and molecular events leading from Dex treatment in EBV-transformed B cells are still not understood completely.…”

Section: Introductionmentioning

confidence: 99%

ROS and ERK1/2-mediated caspase-9 activation increases XAF1 expression in dexamethasone-induced apoptosis of EBV-transformed B cells

Park

Choi

Kim

et al. 2013

International Journal of Oncology

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Dexamethasone (Dex) inhibits the growth of diverse types of cancer cells and is utilized clinically for the therapy of hematological malignancies. In this study, we investigated the molecular mechanisms of Dex action in the apoptosis of Epstein-Barr virus (EBV)-transformed B cells. We showed that Dex inhibited the proliferation of EBV-transformed B cells and induced apoptosis by activating caspase-9, -3 and -8. While activation of caspase-9 was triggered as early as 2 h after Dex treatment, cleavage of caspase-8 was deferred and was found 8 h after the exposure. Dex-dependent activation of caspase-8 was blocked by the specific caspase-9 inhibitor, z-LEHD-fmk. Moreover, Dex significantly increased the expression of X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and induced the translocation of XAF1 into the cytosol. Cytosolic XAF1 with Puma induced the translocation of Bax into mitochondria. Dex led to up-regulation of reactive oxygen species (ROS) generation and the phosphorylation of ERK1/2 after the exposure. We speculated that ROS generation might be the first event of Dex-induced apoptosis because ROS inhibitor NAC abrogated ROS production and ERK1/2 activation, but PD98059 did not block ROS production. NAC and PD98059 also suppressed the translocation of XAF1, Puma and Bax into mitochondria. These results demonstrated that Dex-mediated activation of caspase-9 via ROS generation and ERK1/2 pathway activation resulted in the activation of caspase-8 and the increment of XAF1, thereby induced apoptosis of EBV-transformed B cells. These findings suggest that Dex constitutes a probable therapy for EBV-associated hematological malignancies.

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“…UVR induces PTGS2 in keratinocytes, and the gene is overexpressed in premalignant and malignant nonmelanoma skin lesions [17]. Downregulation of NR3C1 (glucocorticoid receptor) is of interest, as melanoma cells have recently been shown to express this receptor and dexamethasone has an antiproliferative effect on these cells [18]. Other findings were less easily understood.…”

Section: Resultsmentioning

confidence: 99%

Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

Shirley

Grimm²,

Kusewitt

2012

Journal of Skin Cancer

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Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR) component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.

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Glucocorticoid Receptor Expression and Antiproliferative Effect of Dexamethasone on Human Melanoma Cells

Cited by 24 publications

References 26 publications

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism

Stress hormones promote growth of B16-F10 melanoma metastases: an interleukin 6- and glutathione-dependent mechanism

ROS and ERK1/2-mediated caspase-9 activation increases XAF1 expression in dexamethasone-induced apoptosis of EBV-transformed B cells

Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

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