Regulation of the antiapoptotic protein cFLIP by the glucocorticoid Dexamethasone in ALL cells

Kleinesudeik, Lara; Rohde, Katharina; Fulda, Simone

doi:10.18632/oncotarget.24782

Cited by 3 publications

(1 citation statement)

References 45 publications

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“…c-FLIP(L) protein expression is regulated by various events such as the transcriptional, post-transcriptional, and ubiquitin–proteasome system [ 15 , 29 , 30 ]. Interestingly, DEX (300 μM) downregulated c-FLIP(L) protein independent of mRNA expression in acute lymphoblastic leukemia [ 31 ]. However, in our study, DEX-induced c-FLIP(L) downregulation was modulated by transcriptional regulation ( Figure 3 b,c).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Inhibits TRAIL-Induced Apoptosis through c-FLIP(L) Upregulation and DR5 Downregulation by GSK3β Activation in Cancer Cells

Jeon

Woo

Seo

et al. 2020

Cancers

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Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as immunosuppressive and chemotherapeutic agent. This study was undertaken to investigate the effects of DEX on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in cancer cells. We found that upregulation of c-FLIP(L) and downregulation of death receptor 5 (DR5; receptor for TRAIL ligand) contribute to the anti-apoptotic effect of DEX on TRAIL-induced apoptosis. DEX increased c-FLIP(L) expression at the transcriptional levels through the GSK-3β signaling pathway. The pharmacological inhibitor and catalytic mutant of GSK-3β suppressed DEX-induced upregulation of c-FLIP(L) expression. Furthermore, GSK-3β specific inhibitor markedly abolished DEX-mediated reduction of TRAIL-induced apoptosis in human renal cancer cells (Caki-1 and A498), human lung cancer cells (A549), and human breast cancer cells (MDA-MB361). In addition, DEX decreased protein stability of DR5 via GSK-3β-mediated upregulation of Cbl, an E3 ligase of DR5. Knockdown of Cbl by siRNA markedly inhibited DEX-induced DR5 downregulation. Taken together, these results suggest that DEX inhibits TRAIL-mediated apoptosis via GSK-3β-mediated DR5 downregulation and c-FLIP(L) upregulation in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Dexamethasone Inhibits TRAIL-Induced Apoptosis through c-FLIP(L) Upregulation and DR5 Downregulation by GSK3β Activation in Cancer Cells

Jeon

Woo

Seo

et al. 2020

Cancers

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The Combination of Chrysin and Cisplatin Induces Apoptosis in HepG2 through Down-regulation of cFLIP and Activity of Caspase

Luo

Peng

Chen

et al. 2023

ACAMC

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Aim: To investigate the combination effects of chrysin and cisplatin on hepatoma(HepG2) cell lines in vivo and in vitro. Background and Objective: Studies have suggested that Chrysin can enhance sensitivity of tumor cells to apoptosis. Drug resistance in tumor cells reduced the effectiveness of Chemotherapy drug such as Cisplatin. We investigated whether the combination of chrysin and cisplatin can induce more apoptosis than chrysin alone and cisplatin alone. Methods: HepG2 cells were pretreated with chrysin for 2 h, followed by addition of cisplatin for another 24 h. The morphologic changes were observed under inversed microscope and the cell viability was measured using MTT test. The protein and cleavage of caspase-3,8,9,PARP, and cFLIP were determined by Western blotting. Results: The cell viability of the HepG2 cell can be reduced by the combination of chrysin pretreatment for 2h and cisplatin addition for 24 h; Caspase-3,8,9 and PARP were cleaved after 12h treatment with chrysin and cisplatin ; Pan-caspase inhibitor, Z-VAD-fmk, could reversed the apoptosis induced by chrysin and cisplatin in HepG2 cells; cFLIP was down-regulated by the combination of chryin and cisplatin, and could be reversed by Z-VAD-fmk; the xenografted HepG2 cells formed a tumor in one week; At the end of the experiment, there were significant differences in relative tumor volume (RTV) and relative tumor proliferation rate between the combined group and the control group, the chrysin group and the cisplatin group; Western blotting showed that the levels of PARP, cFLIP and caspase-3 proteins in isolated tumor tissues also decreased under the combined action of Chrysin and cisplatin. Conclusion: Combination of chrysin and cisplatin induces apoptosis of hepatic tumor in vivo and in vitro. They down-regulate cFLIP and then activate caspase-8, which triggers caspase-mediated apoptosis of HepG2 cell.

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Saccharomyces cerevisiae RC016 modulates the apoptotic pathways in rat livers treated with aflatoxin B1

Cristofolini

Merkis

Fiorimanti

et al. 2019

WMJ

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The aim was to study the effect of probiotic Saccharomyces cerevisiae RC016 on the expression of apoptotic protein Bax, Bcl-2, DR4 and c-FLIP, in liver of rats exposed to aflatoxin B1 (AFB1). Four treatments were applied to inbred male Wistar rats: uncontaminated feed control, S. cerevisiae RC016 control, contaminated feed with 100 μg/kg AFB1 and contaminated feed with 100 μg/kg AFB1 + daily oral dose 108 viable S. cerevisiae RC016 cells. Histological technique and high-resolution light microscopy (HRLM) were performed to the study of tissue morphology, the TUNEL assay was used to determine the apoptosis cellular and the expression of Bax, Bcl-2, DR4 and c-FLIP was determinate through immunohistochemistry. In liver the necrotic lesions observed with AFB1 treatment were reduced with the addition of yeast. The highest apoptotic index (IAp) was found in the yeast control, with AFB1 decrease significantly the IAp, while with the addition of yeast increase the IAp of liver cells. This was confirmed by HRLM. DR4 receptor was not present in any of the treatments. The immunolabeling of c-FLIP showed a statistically significant increase in the treatments with S. cerevisiae. The extrinsic pathway of apoptosis through the FAS-receptors would neither be active in the apoptotic process observed in rat livers in the treatments with yeast. Significant differences between proteins Bax and Bcl-2 and effect of treatments on the immunolabeling of Bax were determinate. The exposure to AFB1 decreased the IAp in the livers; while the addition of the yeast produced a significant statistically increase of IAp. In this study it was determined that the apoptosis in liver would be induced by the intrinsic pathway through Bax. These suggest that the incorporation of the autocrine strain S. cerevisiae RC016 increases the apoptosis in liver, counteracting the adverse effect of aflatoxin B1 and favouring the tissue remodulation.

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Regulation of the antiapoptotic protein cFLIP by the glucocorticoid Dexamethasone in ALL cells

Cited by 3 publications

References 45 publications

Dexamethasone Inhibits TRAIL-Induced Apoptosis through c-FLIP(L) Upregulation and DR5 Downregulation by GSK3β Activation in Cancer Cells

Dexamethasone Inhibits TRAIL-Induced Apoptosis through c-FLIP(L) Upregulation and DR5 Downregulation by GSK3β Activation in Cancer Cells

The Combination of Chrysin and Cisplatin Induces Apoptosis in HepG2 through Down-regulation of cFLIP and Activity of Caspase

Saccharomyces cerevisiae RC016 modulates the apoptotic pathways in rat livers treated with aflatoxin B1

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