Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2.

23:01 EST 25th November 2014 | BioPortfolio

Summary of "Glucocorticoid receptor antagonist sensitizes TRAIL-induced apoptosis in renal carcinoma cells through up-regulation of DR5 and down-regulation of c-FLIP(L) and Bcl-2."

RU486 (Mifepristone) has been known as antiprogesterone and antiglucocorticoid agent. RU486 is also used for treatment of several cancers, such as breast, ovarian, prostate, and glaucoma. Here, we investigated the effect of RU486 on TRAIL-induced apoptosis in human renal carcinoma Caki cells. Low dose of RU486 (30-50 μM) alone had no effect on apoptosis, but RU486 markedly sensitized Caki cells to TRAIL-induced apoptosis. We found that up-regulation of death receptor 5 (DR5; receptor for TRAIL ligand), and down-regulation of Bcl-2 and c-FLIP (caspase regulator) contributes to RU-486 induced TRAIL sensitization. Down-regulation of DR5 by siRNA also blocked RU486 induced TRAIL sensitization. Furthermore, overexpression of Bcl-1 or c-FLIP(L) inhibited the cell death induced by the combined treatment with RU486 and TRAIL. RU486 increased DR5 expression at the transcriptional levels through induction of CHOP expression. By contrast, RU486 did not sensitize normal human mesangial cells to TRAIL-mediated apoptosis. Effect of RU486 on TRAIL-induced cancer cell apoptosis was independent of glucocorticoid receptor and progesterone receptor. Taken together, RU486 enhances TRAIL-mediated apoptosis through down-regulation of Bcl-2 and c-FLIP(L) as well as CHOP-mediated DR5 up-regulation.

Affiliation

Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.

Journal Details

This article was published in the following journal.

Name: Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Pages:

Links

PubMed Articles [19646 Associated PubMed Articles listed on BioPortfolio]

TRAF2 inhibits TRAIL- and CD95L-induced apoptosis and necroptosis.

The relevance of the adaptor protein TNF receptor-associated factor 2 (TRAF2) for signal transduction of the death receptor tumour necrosis factor receptor1 (TNFR1) is well-established. The role of TR...

Live Free or Die: Cell-Cell Adhesion Regulates Sensitivity to Trail-Induced Apoptosis.

The ability of the death ligand TRAIL to induce tumor cell apoptosis has led to the development of TRAIL-based cancer therapies. Reporting recently in Molecular Cell, Lu et al. (2014) show that the b...

H-Ras regulation of TRAIL death receptor mediated apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitu...

TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications.

Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial a...

Targeting c-Met Receptor Overcomes TRAIL-Resistance in Brain Tumors.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced apoptosis specifically in tumor cells. However, with approximately half of all known tumor lines being resistant to TRAIL, the i...

Clinical Trials [3621 Associated Clinical Trials listed on BioPortfolio]

PREDnisolone-induced Beta-cell Dysfunction Prevented by EXenatide

The purpose of this study is to explore whether the GLP-1 receptor agonist exenatide, may prevent glucocorticoid-induced glucometabolic abnormalities and beta-cell dysfunction in healthy s...

Glucocorticoid Receptor Antagonism in Subclinical Cushings

The purpose of this study is to assess the effects of reducing the activity of endogenous glucocorticoid in patients with low-grade cortisol excess

Comparison of Teriparatide With Alendronate for Treating Glucocorticoid-Induced Osteoporosis

Osteoporosis is a condition in which the amount of bone is reduced, the bones are weak, and there is an increased risk for fractures. Glucocorticoids (such as prednisone) are prescribed t...

Mapatumumab, Cisplatin and Radiotherapy for Advanced Cervical Cancer

Chemoradiotherapy has become the standard of care for women with locally advanced cervical cancer. The available data support a 30 to 50% reduction in the risk of death from cervical cance...

Domperidone as a Treatment for Dopamine Agonist-Induced Peripheral Edema in Patients With Parkinson's Disease

The dopamine agonists, pramipexole (Mirapex) and ropinirole (Requip), are drugs that are used to treat symptoms of Parkinson's disease. However, these drugs can induce bothersome leg swell...

Medical and Biotech [MESH] Definitions

A member of the TNF receptor family that was initially identified as a DEXAMETHASONE-induced protein from a T-CELL line. It may play a role in regulating APOPTOSIS and modulating immune response by T-lymphocytes. Signaling by the activated receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.

A progestational and glucocorticoid hormone antagonist. Its inhibition of progesterone induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium or decidua. As a glucocorticoid receptor antagonist, the drug has been used to treat hypercortisolism in patients with nonpituitary CUSHING SYNDROME.

A widely expressed member of the TNF receptor-associated family that may play a role in neuronal development and EMBRYOGENESIS. Although TNF receptor-associated factor 4 does not strongly associate with TUMOR NECROSIS FACTOR RECEPTORS it may be a signaling partner with the GLUCOCORTICOID-INDUCED TNFR-RELATED PROTEIN that plays a role in the activation of JNK MITOGEN-ACTIVATED PROTEIN KINASES and NF-KAPPA B.

An orphan nuclear receptor that is closely related to members of the thyroid-steroid receptor gene family. It was originally indentified in NERVE CELLS and may play a role in mediation of NERVE GROWTH FACTOR-induced CELL DIFFERENTIATION. However, several other functions have been attributed to this protein including the positive and negative regulation of APOPTOSIS.

Cytoplasmic proteins that specifically bind glucocorticoids and mediate their cellular effects. The glucocorticoid receptor-glucocorticoid complex acts in the nucleus to induce transcription of DNA. Glucocorticoids were named for their actions on blood glucose concentration, but they have equally important effects on protein and fat metabolism. Cortisol is the most important example.

Search BioPortfolio:
Loading
Advertisement

Relevant Topic

Nephrology - kidney function
Latest News Clinical Trials Research Drugs Reports Corporate
Nephrology is a specialty of medicine and pediatrics that concerns itself with the study of normal kidney function, kidney problems, the treatment of kidney problems and renal replacement therapy (dialysis and kidney transplantation). Systemic conditions...

Advertisement