scholarly journals Cratoxylum formosum ssp. pruniflorum activates the TRAIL death receptor complex and inhibits topoisomerase I

2018 ◽  
Vol 114 ◽  
pp. 150-162 ◽  
Author(s):  
A. Nonpunya ◽  
B. Sethabouppha ◽  
S. Rufini ◽  
N. Weerapreeyakul
Keyword(s):  
Topoisomerase I ◽  
Death Receptor ◽  
Receptor Complex ◽  
Trail Death Receptor

Dexamethasone induces pancreatic β-cell apoptosis through upregulation of TRAIL death receptor

2021 ◽  
Author(s):  
Kanchana Suksri ◽  
Namoiy Semprasert ◽  
Mutita Junking ◽  
Suchanoot Kutpruek ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
Death Receptor ◽  
Caspase 8 ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Apoptotic Protein ◽  
Induced Apoptosis ◽  
Trail Death Receptor

Long-term medication with dexamethasone (a synthetic glucocorticoid (GC) drug) results in hyperglycemia, or steroid-induced diabetes. Although recent studies revealed dexamethasone directly induces pancreatic β-cell apoptosis, its molecular mechanisms remain unclear. In our initial analysis of mRNA transcripts, we discovered the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway may be involved in dexamethasone-induced pancreatic β-cell apoptosis. In the present study, a mechanism of dexamethasone-induced pancreatic β-cell apoptosis through the TRAIL pathway was investigated in cultured cells and isolated mouse islets. INS-1 cells were cultured with and without dexamethasone in the presence or absence of a glucocorticoid receptor (GR) inhibitor, RU486. We found that dexamethasone induced pancreatic β-cell apoptosis in association with the upregulation of TRAIL mRNA and protein expression. Moreover, dexamethasone upregulated the TRAIL death receptor (DR5) protein but suppressed the decoy receptor (DcR1) protein. Similar findings were observed in mouse isolated islets: dexamethasone increased TRAIL and DR5 compared to that of control mice. Furthermore, dexamethasone stimulated pro-apoptotic signaling including superoxide production, caspase-8, -9, and -3 activities, NF-B, and Bax, but repressed the anti-apoptotic protein, Bcl-2. All these effects were inhibited by the GR-inhibitor, RU486. Furthermore, knock down DR5 decreased dexamethasone-induced caspase 3 activity. Caspase-8 and caspase-9 inhibitors protected pancreatic β-cells from dexamethasone-induced apoptosis. Taken together, dexamethasone induced pancreatic β-cell apoptosis by binding to the GR and inducing DR5 and TRAIL pathway.

scholarly journals Focal Adhesion Kinase Suppresses Apoptosis by Binding to the Death Domain of Receptor-Interacting Protein

2004 ◽  
Vol 24 (10) ◽  
pp. 4361-4371 ◽  
Author(s):  
Elena Kurenova ◽  
Li-Hui Xu ◽  
Xihui Yang ◽  
Albert S. Baldwin ◽  
Rolf J. Craven ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Death Receptor ◽  
Human Tumors ◽  
Receptor Complex ◽  
Death Domain ◽  
Functional Link ◽  
Interacting Protein ◽  
Survival Signals

ABSTRACT Tumor cells resist the apoptotic stimuli associated with invasion and metastasis by activating survival signals that suppress apoptosis. Focal adhesion kinase (FAK), a tyrosine kinase that is overexpressed in a variety of human tumors, mediates one of these survival signals. Attenuation of FAK expression in tumor cells results in apoptosis that is mediated by caspase 8- and FADD-dependent pathways, suggesting that death receptor pathways are involved in the process. Here, we report a functional link between FAK and death receptors. We have demonstrated that FAK binds to the death domain kinase receptor-interacting protein (RIP). RIP is a major component of the death receptor complex and has been shown to interact with Fas and tumor necrosis factor receptor 1 through its binding to adapter proteins. We have shown that RIP provides proapoptotic signals that are suppressed by its binding to FAK. We thus propose that FAK overexpression in human tumors provides a survival signal function by binding to RIP and inhibiting its interaction with the death receptor complex.

scholarly journals Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 954 ◽  
Author(s):  
Wajant
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Death Receptors ◽  
Maximum Activity ◽  
Receptor Agonists ◽  
Receptor Antibodies ◽  
Trail Death Receptor

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.

scholarly journals Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells

Leukemia ◽  
2021 ◽  
Author(s):  
Min Lu ◽  
Lijuan Xia ◽  
Nada Elmansy ◽  
Cara Clementelli ◽  
Douglas Tremblay ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Drug Targeting ◽  
Patient Survival ◽  
Death Receptor ◽  
Negative Regulator ◽  
Current Therapy ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
The Individual ◽  
Trail Death Receptor

AbstractCurrent therapy for myelofibrosis (MF) results in a limited prolongation of patient survival. In order to improve treatment outcomes, we developed a strategy to effectively deplete MF hematopoietic stem/progenitor cells (HSPCs). In the present study, an imipridone, ONC201, was combined with RG7112, an antagonist of MDM2, a p53 negative regulator, to activate downstream events of the p53 and TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR) pathways. As compared to treatment with the individual drugs, the combination of ONC201 and RG7112 promoted greater degrees of apoptosis of MF CD34+ cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F+ and calreticulin mutated colonies assayed from MF CD34+ cells, but allowed for the persistence or appearance of JAK2 wild type colonies. Treatment with ONC201 combined with RG7112 could be a potentially effective strategy for treating MF patients.

scholarly journals Membrane expression and significance of TRAIL death receptors DR4 and DR5 in Pancreatic cancer

2020 ◽  
Vol 7 (3) ◽  
pp. 54-61
Author(s):  
Dipesh Kumar Yadav ◽  
Ze Sheng Wang ◽  
Yong Fei Hua ◽  
Cai De Lu
Keyword(s):  
Pancreatic Cancer ◽  
Expression Profiles ◽  
Tumor Staging ◽  
Death Receptor ◽  
Receptor Expression ◽  
Stage I ◽  
Membrane Expression ◽  
The Difference ◽  
Well Differentiated ◽  
Trail Death Receptor

Introduction: Tumor necrosis factor related-apoptosis-inducing ligand (TRAIL) is a powerful and selective activator of apoptosis in many cancer cells. We aim to investigate the expression and significance of TRAIL death receptor DR4 and DR5 in pancreatic cancer (PC) tissues. Method: Twenty-eight histologically verified samples of PC tissue were collected between 2018 and 2019. TRAIL death receptor expression profiles were determined by immunohistochemistry. Result: Death receptor DR4 and DR5 were expressed in the PC tissue and the adjacent non-cancerous pancreatic tissues, the expression of DR4 and DR5 in the PC tissue was significantly higher than that of the adjacent non-cancerous pancreatic tissues (p<0.05). Additionally, in both the tissue group, the expression of DR4 was significantly stronger than the DR5 (p<0.05). To assess the relationship between DR4 and DR5 expression, differentiation, and tumor staging of PC, the result reveals that the expression of DR4 and DR5 was significantly higher in stage I tumors than the stage II, III, IV tumors (p<0.05). In contrast, the expression of DR4 and DR5 was decreased with a decrease in the degree of differentiation of tumors. However, the difference was not statistically significant. Conclusion: The membrane expression of TRAIL death receptor DR4 and DR5 is greater in PC than in the adjacent non-cancerous pancreatic tissues. Furthermore, increased membrane expression of TRAIL death receptor DR4 and DR5 in stage I PC and well-differentiated PC may predict the prognosis and feasibility of using TRAIL gene therapy as a treatment option for early PC.

scholarly journals H-Ras regulation of TRAIL death receptor mediated apoptosis

Oncotarget ◽  
2014 ◽  
Vol 5 (13) ◽  
pp. 5125-5137 ◽  
Author(s):  
Jun-Jie Chen ◽  
William P. Bozza ◽  
Xu Di ◽  
Yaqin Zhang ◽  
William Hallett ◽  
...  
Keyword(s):  
Death Receptor ◽  
Trail Death Receptor
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