Dexamethasone suppresses apoptosis in a human gastric cancer cell line through modulation of <i>bcl‐x</i> gene expression

Chang, Tsu‐Chung; Hung, Mei-Whey; Jiang, Shu-Yang; Chu, Jing-Tsai; Chu, Li-Ling; Tsai, Li-Ping

doi:10.1016/s0014-5793(97)01083-1

Cited by 53 publications

(40 citation statements)

References 20 publications

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“…The enhanced bcl-xL mRNA and protein levels in rat hepatocytes appear to represent a part of the mechanism underlying the protective effect of DEX. Chang et al, 51 showed that the expression of the bcl-x gene in TMK-1 cells is regulated by DEX at both posttranscriptional and translational levels. Our results indicate that transcriptional mechanisms are important.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

Bailly-Maître¹,

Sousa²,

Boulukos³

et al. 2001

Cell Death Differ

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We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression. Cell Death and Differentiation (2001) 8, 279 ± 288.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

Bailly-Maître¹,

Sousa²,

Boulukos³

et al. 2001

Cell Death Differ

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“…To verify that both splice variants were being affected over the time periods presented, we used a ribonuclease protection assay that was highly quantitative. Using this assay, Bcl-x(L) was shown to decrease with ceramide treatment (following the published half-life of ϳ14 h for Bcl-x(L) mRNA) as well as caspase 9b while caspase 9 and Bcl-x(s) were both demonstrated to in- crease significantly (67,68). Since both splice variants are affected in response to ceramide, transcriptional effects are an unlikely mechanism of action as both splice variants would be affected in the same direction.…”

Section: Exogenous Ceramide Regulates the Alternative Splicing Ofmentioning

confidence: 94%

De Novo Ceramide Regulates the Alternative Splicing of Caspase 9 and Bcl-x in A549 Lung Adenocarcinoma Cells

Chalfant

Rathman

Pinkerman

et al. 2002

Journal of Biological Chemistry

315

287

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Previous studies have demonstrated that several splice variants are derived from both the caspase 9 and Bcl-x genes in which the Bcl-x splice variant, Bcl-x(L) and the caspase 9 splice variant, caspase 9b, inhibit apoptosis in contrast to the pro-apoptotic splice variants, Bcl-x(s) and caspase 9. In a recent study, we showed that ceramide induces the dephosphorylation of SR proteins, a family of protein factors that regulate alternative splicing. In this study, the regulation of the alternative processing of pre-mRNA of both caspase 9 and Bcl-x(L) was examined in response to ceramide. Treatment of A549 lung adenocarcinoma cells with cellpermeable ceramide, D-e-C 6 ceramide, down-regulated the levels of Bcl-x(L) and caspase 9b mRNA and immunoreactive protein with a concomitant increase in the mRNA and immunoreactive protein levels of Bcl-x(s) and caspase 9 in a dose-and time-dependent manner. Pretreatment with calyculin A (5 nM), an inhibitor of protein phosphatase-1 (PP1) and protein phosphatase 2A (PP2A) blocked ceramide-induced alternative splicing in contrast to okadaic acid (10 nM), a specific inhibitor of PP2A at this concentrations in cells, demonstrating a PP1-mediated mechanism. A role for endogenous ceramide in regulating the alternative splicing of caspase 9 and Bcl-x was demonstrated using the chemotherapeutic agent, gemcitabine. Treatment of A549 cells with gemcitabine (1 M) increased ceramide levels 3-fold via the de novo sphingolipid pathway as determined by pulse labeling experiments and inhibition studies with myriocin (50 nM), a specific inhibitor of serine palmitoyltransferase (the first step in de novo synthesis of ceramide). Treatment of A549 cells with gemcitabine downregulated the levels of Bcl-x(L) and caspase 9b mRNA with a concomitant increase in the mRNA levels of Bclx(s) and caspase 9. Again, inhibitors of ceramide synthesis blocked this effect. We also demonstrate that the change in the alternative splicing of caspase 9 and Bcl-x occurred prior to apoptosis following treatment with gemcitabine. Furthermore, doses of D-e-C 6 ceramide that induce the alternative splicing of both caspase 9 and Bcl-x-sensitized A549 cells to daunorubicin. These data demonstrate a role for protein phosphatases 1 (PP1) and endogenous ceramide generated via the de novo pathway in regulating this mechanism. This is the first report on the dynamic regulation of RNA splicing of members of the Bcl-2 and caspase families in response to regulators of apoptosis.

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“…Glucocorticoids were found to enhance the cytotoxicity of cisplatin via suppression of NF-κB activation in the GR-rich human cervical carcinoma cell line SiHa [88,89]. On the other hand, other studies have shown that glucocorticoids decrease the chemosensitivity in non-hematological solid tumors cells through a variety of mechanisms, which include the modulation of bcl-x gene expression, and the up-regulation of p21 Cip1 and mitogenactivated protein kinase phosphatase-1 (MKP-1) [22,97,159].…”

Section: Pre-clinical and Clinical Trials Of Nf-κb Inhibitorsmentioning

confidence: 99%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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Abstract. Nuclear factor κB (NF-κB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-κB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-κB activation which mediates resistance to chemo-and radio-therapy. Therefore, the inhibition of NF-κB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-κB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-κB in carcinogenesis and the therapeutic potential of targeting NF-κB in cancer therapy.Keywords: NF-κB, NF-κB inhibitor, carcinogenesis, cancer therapy Structure, function and regulation of NF-κBNuclear factor-κB (NF-κB) was first identified in 1986 as a transcription factor that binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [128]. The mammalian NF-κB family consists of 5 members: NF-κB1 (p50/p105), NF-κB2 (p52/p100), c-Rel, RelA (p65) and RelB (Fig. 1). RelA, c-Rel and RelB are synthesized in their mature forms and contain a transactivation domain that interacts with the transcriptional apparatus. On the other hand, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) are synthesized in precursor forms (p100 and p105) which contain C-terminal ankyrin repeats that are proteolysed by the proteasome resulting in the production of mature proteins (p50 and p52). Both p50 and p52 contain a DNA binding domain but lack a transactivation domain. NF-κB proteins exist in unstimulated cells as homo-or heterodimers bound to IκB proteins. Whereas RelB forms only heterodimers, all the other proteins can form both homo-and heterodimers. NF-κB proteins are characterized by the presence of a highly conserved 300 amino acid Rel homology domain that is located toward the N terminus of the protein, and which is responsible for DNA binding, dimerization, and interaction with specific inhibitory factors known as IκB proteins [7,36].

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Dexamethasone suppresses apoptosis in a human gastric cancer cell line through modulation of bcl‐x gene expression

Cited by 53 publications

References 20 publications

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

De Novo Ceramide Regulates the Alternative Splicing of Caspase 9 and Bcl-x in A549 Lung Adenocarcinoma Cells

NF‐κB as a potential molecular target for cancer therapy

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