Dexamethasone inhibits TNF‐α‐induced apoptosis and IAP protein downregulation in MCF‐7 cells

Meßmer, Udo K.; Pereda-Fernández, Carmen; Manderscheid, Markus; Pfeilschifter, Josef

doi:10.1038/sj.bjp.0704093

Cited by 63 publications

(56 citation statements)

References 51 publications

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“…Therefore, it would appear that the action of Dex is not specific to modulating the effect of statin on the cell cycle, rather it would seem that Dex blocks endothelial cell apoptosis. This finding is consistent with some of the recent literature including our own (Newton et al 2001) that glucocorticoids block apoptosis in other cell systems (Messmer et al 2001, Mikosz et al 2001, Sasson et al 2001, Zhang et al 2001. Table 2 provides data that strongly support the idea that the effect of Dex is to block apoptosis at a common element in the pathway.…”

Section: Discussionsupporting

confidence: 82%

Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Newton

Ran²,

Xie³

et al. 2002

Journal of Endocrinology

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Statins block de novo synthesis of cholesterol by inhibiting the enzyme, HMG CoA reductase. The product of this reaction, mevalonic acid, is also a precursor of isoprenoids, molecules required for the activation of signalling G-proteins, such as Ras. Signal transduction pathways involving Ras are important for cell survival and this may be why statins induce apoptotic death of several cell types. Given that statins are used to treat vascular disease, it is surprising that no studies have been conducted on vascular endothelial cells. For this reason, we have tested the effect of fluvastatin (FS) on the endothelial cell line EA.hy 926. Here we show that FS, at concentrations from 1 to 2 µM, blocks growth and induces apoptosis of the endothelial cell line, EA.hy 926. As considerable redundancy exists in cell signalling pathways for cell survival, toxicity of FS under more physiological conditions might be prevented by pathways that do not require Ras, such as those activated by adrenal or sex steroids. To test this hypothesis, first RT-PCR analysis was performed for nuclear receptor mRNA expression. This revealed the presence of mRNA for the androgen receptor (AR) and glucocorticoid receptor (GR). The effect of the AR agonist, dihydrotestosterone (DHT), and the GR agonist, dexamethasone (Dex), was then tested. Whilst DHT (100 nM) had no effect on FS-induced cell death, Dex (1 µM) blocked FS-induced apoptosis. Cell cycle analysis revealed that 24 h exposure to FS prevented cells from leaving G 1 and 24-48 h later a marked sub-G 1 peak was observed. Dex was able to reduce the sub-G 1 peak, but it failed to reduce accumulation of cells in G 1 . Further studies revealed that, in addition to blocking FS-induced apoptosis, Dex was able to block apoptosis of EA.hy 926 cells induced by serum deprivation, tumour necrosis factor-, oxidants, DNA damage and mitochondrial disruption. This study strongly suggests that glucocorticoids have a role to play in preventing vascular injury and they may provide a reason why statins are apparently not toxic to vascular endothelial cells in vivo.

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Section: Discussionsupporting

confidence: 82%

Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Newton

Ran²,

Xie³

et al. 2002

Journal of Endocrinology

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“…IGFBP-3-Induced Apoptosis Is Mediated by Caspase-Dependent Pathways. Previous studies have demonstrated that exposure of MCF-7cells to TNF-␣ (25-50 ng/ml) leads to apoptotic cell death (30 -60%) within 24 h (43). In the present study, cells treated with 20 ng/ml TNF-␣ or 15 M ponasterone A both showed a marked decrease in proliferation (Fig.…”

Section: Igfbp-3 Induces Apoptosis Via Activation Of Caspasessupporting

confidence: 55%

Insulin-Like Growth Factor-Binding Protein 3 Induces Caspase-Dependent Apoptosis through a Death Receptor-Mediated Pathway in MCF-7 Human Breast Cancer Cells

et al. 2004

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Insulin-like growth factor-binding protein (IGFBP)-3 has been shown to potently inhibit cell proliferation in various cell systems. However, the specific mechanisms involved in the antiproliferative action of IGFBP-3 have yet to be elucidated. In the present study, we demonstrate that IGFBP-3 induces apoptosis in an insulin-like growth factor (IGF)-independent manner through the activation of caspases involved in a death receptor-mediated pathway in MCF-7 human breast cancer cells. Induction of IGFBP-3 using an ecdysone-inducible expression system inhibited DNA synthesis in an IGF-IGF receptor axis-independent fashion and resulted in the subsequent induction of apoptosis and an increase in caspase activity. Similar results were obtained when cells were transfected with GGG-IGFBP-3, an IGFBP-3 mutant unable to bind IGFs, corroborating the IGF-independent action of IGFBP-3. Additional caspase activity studies and immunoblot analyses using specific caspase substrates and/or caspase inhibitors revealed that the growth-inhibitory effect of IGFBP-3 results mainly from its induction of apoptosis (in particular, activation of caspase-8 and -7). Analyses of caspase-9 activity and release of cytochrome c into the cytosol confirmed that the mitochondria-mediated pathway is not involved. Taken together, these results show that IGFBP-3 expression leads to the induction of apoptosis through the activation of caspases involved in a death receptor-mediated pathway and that IGFBP-3 functions as a negative regulator of breast cancer cell growth, independent of the IGF-IGF receptor axis.

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“…Interestingly, the morphological phenotype and cell detachment generated by the full-length caspase-resistant (MST1(D326N)) and truncated (MST1-(1-326)) constructs were indistinguishable from those elicited by the MST1(WT) kinase. MST1 kinase activity thus seems to be both necessary and sufficient to produce morphological changes, in contrast to chromatin condensation, which requires MST1 caspase cleavage or expression of the truncated species (26).…”

Section: Cloning and Expression Of Mst1-mst1mentioning

confidence: 99%

Mapping of MST1 Kinase Sites of Phosphorylation

Glantschnig

Rodan

Reszka

2002

Journal of Biological Chemistry

165

171

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MST1 is a member of theIn mammalian cells, Sterile-20 (Ste20)-related kinases participate in the regulation of the cytoskeleton that controls cell morphology and motility, and in the regulation of apoptosis (1). These kinases share a conserved catalytic (kinase) domain at the amino terminus and a C-terminal regulatory region of great structural diversity, which interacts with signaling molecules that regulate the cytoskeleton. Currently, four closely related MST kinases have been described (5-9). Most Ste20 group kinases activate mitogen-activated protein kinase (MAPK) 1 cascades in the signaling pathways between the cellular membrane and the nuclear compartment (2). In yeast, the mating pheromone receptor Ste20p phosphorylates and activates a MAPK kinase kinase, Ste11p, raising the possibility that mammalian homologs of Ste20p (e.g. MST1 kinase) also function as MAPK kinase kinase kinases (3, 4). MST1 was shown to act upstream of MAPK kinases that regulate p38 and JNK activities, probably acting via the MAPK kinase kinase MEKK1 (10).There is substantial evidence that MST1 promotes apoptosis, although its role in this process may vary in different cell types. Overexpression of MST1 can induce apoptosis and nuclear condensation in BJAB, 293T and COS-1 cells (4, 14, 15), whereas MST1 promotes nuclear condensation without apparent chromosomal cleavage in HeLa cells (13).A consistent feature of MST1 in all tested cell types is its proteolytic cleavage by caspase, in response to apoptotic stimuli, to a 34 -36-kDa product (hereafter referred to as 36-kDa MST1). Cleavage increases MST1 kinase activity severalfold (4, 16 -19) and influences its subcellular localization (13, 15). Recently, a second caspase cleavage site was identified in the human MST1 sequence that is absent in mouse MST1 and in MST2 from several species (10). Mutation of this site has no impact on accumulation of the 36-kDa species.Expression of a kinase-dead MST1 mutant (K59R) can partially or fully suppress apoptosis or chromatin condensation in HL-60 and 293T cells treated with chemical apoptotic stimuli (15,18). This protective effect is associated with suppression of both JNK activity and DNA fragmentation. However, the K59R mutant fails to suppress apoptosis in BJAB and HeLa cells treated with Fas ligand or TNF-␣ (4, 16). The basis for the cell type-and stimulus-specific differences in MST function has not yet been elucidated.Interestingly, like PAK proteins (11, 12), MST1 (full-length or cleaved) can have a profound effect on cell shape (cell rounding and detachment) independent of caspase activation and prior to nuclear condensation (13). This action and the high basal activity of MST1 kinase suggest a possible function unrelated to apoptosis.Stress-inducing agents such as staurosporine and sodium arsenite (9) can increase MST1 kinase activity; however, no physiological activator of MST1 has been identified, and little is known about the endogenous activation of MST1. Recently, it was proposed that in addition to caspase cleavage, MST1 phosphor...

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Dexamethasone inhibits TNF‐α‐induced apoptosis and IAP protein downregulation in MCF‐7 cells

Cited by 63 publications

References 51 publications

Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Insulin-Like Growth Factor-Binding Protein 3 Induces Caspase-Dependent Apoptosis through a Death Receptor-Mediated Pathway in MCF-7 Human Breast Cancer Cells

Mapping of MST1 Kinase Sites of Phosphorylation

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