TRAIL-death receptor endocytosis and apoptosis are selectively regulated by dynamin-1 activation

Clathrin-mediated endocytosis (CME) constitutes the major pathway for uptake of signaling receptors into eukaryotic cells. As such, CME regulates signaling from cell-surface receptors, but whether and how specific signaling receptors reciprocally regulate the CME machinery remains an open question. Although best studied for its role in membrane fission, the GTPase dynamin also regulates early stages of CME. We recently reported that dynamin-1 (Dyn1), previously assumed to be neuron-specific, can be selectively activated in cancer cells to alter endocytic trafficking. Here we report that dynamin isoforms differentially regulate the endocytosis and apoptotic signaling downstream of TNF-related apoptosis-inducing ligand–death receptor (TRAIL–DR) complexes in several cancer cells. Whereas the CME of constitutively internalized transferrin receptors is mainly dependent on the ubiquitously expressed Dyn2, TRAIL-induced DR endocytosis is selectively regulated by activation of Dyn1. We show that TRAIL stimulation activates ryanodine receptor-mediated calcium release from endoplasmic reticulum stores, leading to calcineurin-mediated dephosphorylation and activation of Dyn1, TRAIL–DR endocytosis, and increased resistance to TRAIL-induced apoptosis. TRAIL–DR-mediated ryanodine receptor activation and endocytosis is dependent on early caspase-8 activation. These findings delineate specific mechanisms for the reciprocal crosstalk between signaling and the regulation of CME, leading to autoregulation of endocytosis and signaling downstream of surface receptors.

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Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism

Scientific Reports ◽

10.1038/s41598-019-56675-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Betty Yuen Kwan Law ◽

Francesco Michelangeli ◽

Yuan Qing Qu ◽

Su-Wei Xu ◽

Yu Han ◽

...

Keyword(s):

Cell Death ◽

Cancer Therapy ◽

Cancer Cells ◽

Ryanodine Receptor ◽

Calcium Release ◽

Receptor Activation ◽

Autophagic Cell Death ◽

Dependent Manner ◽

Computational Docking ◽

Calcium Dependent

AbstractResistance of cancer cells to chemotherapy is a significant clinical concern and mechanisms regulating cell death in cancer therapy, including apoptosis, autophagy or necrosis, have been extensively investigated over the last decade. Accordingly, the identification of medicinal compounds against chemoresistant cancer cells via new mechanism of action is highly desired. Autophagy is important in inducing cell death or survival in cancer therapy. Recently, novel autophagy activators isolated from natural products were shown to induce autophagic cell death in apoptosis-resistant cancer cells in a calcium-dependent manner. Therefore, enhancement of autophagy may serve as additional therapeutic strategy against these resistant cancers. By computational docking analysis, biochemical assays, and advanced live-cell imaging, we identified that neferine, a natural alkaloid from Nelumbo nucifera, induces autophagy by activating the ryanodine receptor and calcium release. With well-known apoptotic agents, such as staurosporine, taxol, doxorubicin, cisplatin and etoposide, utilized as controls, neferine was shown to induce autophagic cell death in a panel of cancer cells, including apoptosis-defective and -resistant cancer cells or isogenic cancer cells, via calcium mobilization through the activation of ryanodine receptor and Ulk-1-PERK and AMPK-mTOR signaling cascades. Taken together, this study provides insights into the cytotoxic mechanism of neferine-induced autophagy through ryanodine receptor activation in resistant cancers.

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Caspase-8 deficiency induces a switch from TLR3 induced apoptosis to lysosomal cell death in neuroblastoma

Scientific Reports ◽

10.1038/s41598-021-89793-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie-Anaïs Locquet ◽

Gabriel Ichim ◽

Joseph Bisaccia ◽

Aurelie Dutour ◽

Serge Lebecque ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Neuroblastoma Cell ◽

Death Receptor ◽

Neuroblastoma Cell Line ◽

Caspase 8 ◽

Caspase Activation ◽

Extrinsic Pathway ◽

Lysosomal Membrane Permeabilization ◽

Induced Apoptosis

AbstractIn cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a “default” death mechanism in cancer cells, when Caspase-8 is absent and apoptosis cannot be induced.

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CSC ‐3436 sensitizes triple negative breast cancer cells to TRAIL ‐induced apoptosis through ROS ‐mediated p38/ CHOP /death receptor 5 signaling pathways

Environmental Toxicology ◽

10.1002/tox.23372 ◽

2021 ◽

Author(s):

Chun‐Chen Huang ◽

Yi‐Ching Cheng ◽

Ying‐Chao Lin ◽

Chun‐Hung Chou ◽

Chi‐Tang Ho ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Death Receptor ◽

Death Receptor 5 ◽

Induced Apoptosis

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Ciprofloxacin Enhances TRAIL-Induced Apoptosis in Lung Cancer Cells by Upregulating the Expression and Protein Stability of Death Receptors through CHOP Expression

International Journal of Molecular Sciences ◽

10.3390/ijms19103187 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3187 ◽

Cited By ~ 8

Author(s):

Eun Lim ◽

Yu Yoon ◽

Jeonghoon Heo ◽

Tae Lee ◽

Young-Ho Kim

Keyword(s):

Lung Cancer ◽

Protein Stability ◽

Cancer Cells ◽

Death Receptor ◽

Proteolytic Processing ◽

Receptor Expression ◽

Host Cells ◽

Lung Cancer Cells ◽

Regulation Of Transcription ◽

Induced Apoptosis

Ciprofloxacin (CIP) is a potent antimicrobial agent with multiple effects on host cells and tissues. Previous studies have highlighted their proapoptotic effect on human cancer cells. The current study showed that subtoxic doses of CIP effectively sensitized multiple cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated the partial proteolytic processing of procaspase-3 in lung cancer cells, co-treatment with CIP and TRAIL efficiently restored the complete activation of caspases. We found that treatment of lung cancer with CIP significantly upregulated the expression and protein stability of death receptor (DR) 5. These effects were mediated through the regulation of transcription factor CCAT enhancer-binding protein homologous protein (CHOP) since the silencing of these signaling molecules abrogated the effect of CIP. Taken together, these results indicated that the upregulation of death receptor expression and protein stability by CIP contributed to the restoration of TRAIL-sensitivity in lung cancer cells.

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p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-related Apoptosis-inducing Ligand Expression

10.20944/preprints201908.0182.v1 ◽

2019 ◽

Author(s):

Matharage Gayani Dilshara ◽

Ilandarage Menu Neelaka Molagoda ◽

Rajapaksha Gedara Prasad Tharanga Jayasooriya ◽

Yung Hyun Choi ◽

Cheol Park ◽

...

Keyword(s):

Cancer Cells ◽

Death Receptor ◽

Chimeric Antibody ◽

Ros Production ◽

Death Receptor 5 ◽

Homologous Protein ◽

Anti Cancer ◽

Ligand Expression ◽

Induced Apoptosis ◽

Factor C

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

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Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms131115343 ◽

2012 ◽

Vol 13 (12) ◽

pp. 15343-15359 ◽

Cited By ~ 26

Author(s):

Ewelina Szliszka ◽

Dagmara Jaworska ◽

Małgorzata Ksek ◽

Zenon Czuba ◽

Wojciech Król

Keyword(s):

Cancer Cells ◽

Death Receptor ◽

Induced Apoptosis ◽

Apoptosis In Cancer Cells

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N-Acetyl-Glucosamine Sensitizes Non-Small Cell Lung Cancer Cells to TRAIL-Induced Apoptosis by Activating Death Receptor 5

Cellular Physiology and Biochemistry ◽

10.1159/000488042 ◽

2018 ◽

Vol 45 (5) ◽

pp. 2054-2070 ◽

Cited By ~ 10

Author(s):

Ye Liang ◽

Wenhua Xu ◽

Shihai Liu ◽

Jingwei Chi ◽

Jisheng Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Sodium Dodecyl ◽

Death Receptor ◽

Small Cell ◽

Clinical Samples ◽

Small Cell Lung ◽

Induced Apoptosis

Background/Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer agent due to its selective toxicity. However, many human non-small cell lung cancer (NSCLC) cells are partially resistant to TRAIL, thereby limiting its clinical application. Therefore, there is a need for the development of novel adjuvant therapeutic agents to be used in combination with TRAIL. Methods: In this study, the effect of N-acetyl-glucosamine (GlcNAc), a type of monosaccharide derived from chitosan, combined with TRAIL was evaluated in vitro and in vivo. Thirty NSCLC clinical samples were used to detect the expression of death receptor (DR) 4 and 5. After GlcNAc and TRAIL co-treatment, DR expression was determined by real-time PCR and western blotting. Cycloheximide was used to detect the protein half-life to further understand the correlation between GlcNAc and the metabolic rate of DR. Non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to detect receptor clustering, and the localization of DR was visualized by immunofluorescence under a confocal microscope. Furthermore, a co-immunoprecipitation assay was performed to analyze the formation of death-inducing signaling complex (DISC). O-linked glycan expression levels were evaluated following DR5 overexpression and RNA interference mediated knockdown. Results: We found that the clinical samples expressed higher levels of DR5 than DR4, and GlcNAc co-treatment improved the effect of TRAIL-induced apoptosis by activating DR5 accumulation and clustering, which in turn recruited the apoptosis-initiating protease caspase-8 to form DISC, and initiated apoptosis. Furthermore, GlcNAc promoted DR5 clustering by improving its O-glycosylation. Conclusion: These results uncovered the molecular mechanism by which GlcNAc sensitizes cancer cells to TRAIL-induced apoptosis, thereby highlighting a novel effective agent for TRAIL-mediated NSCLC-targeted therapy.

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Artemisinin Derivatives Stimulate DR5-Specific TRAIL-Induced Apoptosis by Regulating Wildtype P53

Cancers ◽

10.3390/cancers12092514 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2514

Author(s):

Xinyu Zhou ◽

Sietske N. Zijlstra ◽

Abel Soto-Gamez ◽

Rita Setroikromo ◽

Wim J. Quax

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Death Receptor ◽

Dependent Manner ◽

Death Receptor 5 ◽

Novel Therapy ◽

Artemisinin Derivatives ◽

The Status ◽

Cervical Cancer Cells ◽

Induced Apoptosis

Artemisinin derivatives, widely known as commercial anti-malaria drugs, may also have huge potential in treating cancer cells. It has been reported that artemisinin derivatives can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in liver and cervical cancer cells. In our study, we demonstrated that artesunate (ATS) and dihydroartemisinin (DHA) are more efficient in killing colon cancer cells compared to artemisinin (ART). ATS/DHA induces the expression of DR5 in a P53 dependent manner in HCT116 and DLD-1 cells. Both ATS and DHA overcome the resistance to DHER-induced apoptosis in HCT116, mainly through upregulating death receptor 5 (DR5). We also demonstrate that DHA sensitizes HCT116 cells to DHER-induced apoptosis via P53 regulated DR5 expression in P53 knockdown assays. Nevertheless, a lower effect was observed in DLD-1 cells, which has a single Ser241Phe mutation in the P53 DNA binding domain. Thus, the status of P53 could be one of the determinants of TRAIL resistance in some cancer cells. Finally, the combination treatment of DHA and the TRAIL variant DHER increases cell death in 3D colon cancer spheroid models, which shows its potential as a novel therapy.

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