scholarly journals Dihydroartemisinin promotes CHAC1 transcription to induce ferroptosis in primary liver cancer cells: activation of unfolded protein responses

2020 ◽  
Author(s):  
Zhiwei Wang ◽  
Mingxing Li ◽  
Yuanfeng Liu ◽  
Zhentao Qiao ◽  
Tao Bai ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Cancer ◽  
Primary Liver Cancer ◽  
Iron Ions ◽  
Unfolded Protein ◽  
Liver Cancer Cells ◽  
Deferoxamine Mesylate ◽  
P53 Status ◽  
Protein Response

Abstract Background: This study aimed to explore whether dihydroartemisinin (DHA), an artemisinin derivate drug, eliminates primary liver cancer (PLC) cells by inducing ferroptosis. Methods: Four PLC cell lines were treated with varied concentrations of DHA. RNA interference was performed to knock down the expression of unfolded protein response (UPR) sensors in vitro. Results: DHA-caused PLC cell death was irrelevant to p53 status. PLC cells exposed to DHA displayed classic ferroptosis features – increased lipid ROS, MDA and iron ions, and decreased activity or expression of GSH, GPX4, SLC7A11 and SLC3A2. The anti-tumor effects of DHA were significantly weakened by ferrostatin-1 and deferoxamine mesylate salt, but augmented by iron overload. DHA activated all three UPR branches, including PERK/eIF2/ATF4, IRE1α / XBP1 , and ATF6, in vitro . Further, to deactivate UPRs, exclusive siRNA was used to silence the expression of ATF4, XBP1 or ATF6 in PLC cells. Unexpectedly, ferroptosis induced by DHA was significantly attenuated when ATF4, XBP1 or ATF6 was knocked down. The transcription of CHAC1, a molecule that is capable of degrading GSH, was enhanced by DHA, but weakened when the above three UPR transcription factors were silenced.Conclusion: DHA effectively induces ferroptosis in PLC cells, which involves the activation of anti-survival UPRs.

scholarly journals A Novel Transcription Factor, ERD15 (Early Responsive to Dehydration 15), Connects Endoplasmic Reticulum Stress with an Osmotic Stress-induced Cell Death Signal

2011 ◽  
Vol 286 (22) ◽  
pp. 20020-20030 ◽  
Author(s):  
Murilo S. Alves ◽  
Pedro A. B. Reis ◽  
Silvana P. Dadalto ◽  
Jerusa A. Q. A. Faria ◽  
Elizabeth P. B. Fontes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Er Stress ◽  
Unfolded Protein ◽  
Eukaryotic Organisms ◽  
Protein Response

As in all other eukaryotic organisms, endoplasmic reticulum (ER) stress triggers the evolutionarily conserved unfolded protein response in soybean, but it also communicates with other adaptive signaling responses, such as osmotic stress-induced and ER stress-induced programmed cell death. These two signaling pathways converge at the level of gene transcription to activate an integrated cascade that is mediated by N-rich proteins (NRPs). Here, we describe a novel transcription factor, GmERD15 (Glycine max Early Responsive to Dehydration 15), which is induced by ER stress and osmotic stress to activate the expression of NRP genes. GmERD15 was isolated because of its capacity to stably associate with the NRP-B promoter in yeast. It specifically binds to a 187-bp fragment of the NRP-B promoter in vitro and activates the transcription of a reporter gene in yeast. Furthermore, GmERD15 was found in both the cytoplasm and the nucleus, and a ChIP assay revealed that it binds to the NRP-B promoter in vivo. Expression of GmERD15 in soybean protoplasts activated the NRP-B promoter and induced expression of the NRP-B gene. Collectively, these results support the interpretation that GmERD15 functions as an upstream component of stress-induced NRP-B-mediated signaling to connect stress in the ER to an osmotic stress-induced cell death signal.

scholarly journals Highlighting Curcumin-Induced Crosstalk between Autophagy and Apoptosis as Supported by Its Specific Subcellular Localization

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 361 ◽  
Author(s):  
Francisco J. Sala de Oyanguren ◽  
Nathan E. Rainey ◽  
Aoula Moustapha ◽  
Ana Saric ◽  
Franck Sureau ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Calcium Release ◽  
Curcuma Longa ◽  
Cancer Cell Growth ◽  
Unfolded Protein ◽  
The Status ◽  
Type Ii Cell ◽  
Protein Response

Curcumin, a major active component of turmeric (Curcuma longa, L.), is known to have various effects on both healthy and cancerous tissues. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effect of curcumin is still unclear. Since there is a recent consensus about endoplasmic reticulum (ER) stress being involved in the cytotoxicity of natural compounds, we have investigated using Image flow cytometry the mechanistic aspects of curcumin’s destabilization of the ER, but also the status of the lysosomal compartment. Curcumin induces ER stress, thereby causing an unfolded protein response and calcium release, which destabilizes the mitochondrial compartment and induce apoptosis. These events are also associated with secondary lysosomal membrane permeabilization that occurs later together with an activation of caspase-8, mediated by cathepsins and calpains that ended in the disruption of mitochondrial homeostasis. These two pathways of different intensities and momentum converge towards an amplification of cell death. In the present study, curcumin-induced autophagy failed to rescue all cells that underwent type II cell death following initial autophagic processes. However, a small number of cells were rescued (successful autophagy) to give rise to a novel proliferation phase.

scholarly journals P09.14 Blocking counterregulation of unfolded protein response by targeted protein synthesis inhibition produces highly synergistic cell death in several cancer entities

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A59.1-A59
Author(s):  
F Gsottberger ◽  
C Meier ◽  
S Petkovic ◽  
L Mellenthin ◽  
M Krumbholz ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Unfolded Protein Response ◽  
Therapeutic Window ◽  
Protein Synthesis Inhibition ◽  
Synthesis Inhibition ◽  
Unfolded Protein ◽  
Protein Response

BackgroundBecause tumor cells have high proliferation rates the demand for energy on the one hand and proteins on the other hand is high. In line, protein folding machinery of the ER is heavily used. 2-Deoxyglucose (2-DG) not only blocks energy synthesis by inhibiting glycolysis but also blocks synthesis of mannosyl leading to impaired N-linked glycosylation, accumulation of misfolded proteins, and increased unfolded protein response (UPR). However, due to compensatory events, UPR-induced apoptosis is hampered. Therefore, we combined 2-DG with targeted protein synthesis inhibition by immunotoxins, consisting of an antibody and pseudomonas exotoxin, to enhance UPR mediated cell death.Materials and MethodsEstablished cell lines and patient-derived B-ALL samples were treated in vitro with various protein synthesis inhibitors and UPR-inducers. Drug synergy was determined mathematically as fold-increase over additivity. Biochemical studies were performed using western blots. In vivo enhancement was tested using systemic xenograft models.ResultsThe combination of Moxetumomab and 2-DG achieved a two to nine-fold synergy in vitro. Synergy was abrogated by the addition of Mannose suggesting UPR as cause of synergistic cell death. Similarly, Moxetumomab enhanced UPR-inducers Bortezomib and tunicamycin and protein synthesis inhibition by cycloheximide and puromycin enhanced 2-DG suggesting a conserved mechanism. Using HB21, an immunotoxin targeting human transferrin-receptor, breast cancer, hepatocellular carcinoma, and glioblastoma were sensitized to 2-DG induced cell death. Biochemically, 2-DG increased XBP-1-cleavage, expression of pro-apoptotic CHOP and of anti-apoptotic BIP. Moxetumomab, however, blocked the upregulation of BIP while maintaining CHOP correlating with synergistic increase in PARP-cleavage and apoptosis. In two systemic mouse models, bone marrow (BM) lymphoma infiltration was not reduced by 2-DG or tunicamycin alone but was reduced after treatment with Moxetumomab alone by 5-fold in the JeKo-1 and by 16-fold in the Ramos model, respectively. The combination of Moxetumomab and 2-DG achieved a three-fold synergy in the JeKo-1 model and achieved MRD-negative BM status in the Ramos model. Against patient-derived B-ALL of the Burkitt’s type, 2-DG and Moxetumomab were up to 5-fold more active in vitro and up to 7-fold more active in mouse xenografts in vivo.ConclusionsCell death after persisting unfolded protein response is synergistically enhanced by tumor-cell specific inhibition of protein synthesis against four distinct tumor entities at physiologically achievable concentrations. Our approach of immunotoxin-induced targeted protein synthesis inhibition opens a novel, so far undescribed therapeutic window which may warrant clinical evaluation.Disclosure InformationF. Gsottberger: None. C. Meier: None. S. Petkovic: None. L. Mellenthin: None. M. Krumbholz: None. M. Metzler: None. A. Mackensen: None. F. Müller: None.

scholarly journals Nodulin 22, a Novel Small Heat-Shock Protein of the Endoplasmic Reticulum, Is Linked to the Unfolded Protein Response in Common Bean

2014 ◽  
Vol 27 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Jonathan Rodriguez-López ◽  
Cynthia Martínez-Centeno ◽  
Annamalai Padmanaban ◽  
Gabriel Guillén ◽  
Juan Elías Olivares ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Heat Shock ◽  
Common Bean ◽  
Unfolded Protein Response ◽  
Reverse Genetics ◽  
Virus Induced Gene Silencing ◽  
Unfolded Protein ◽  
Protein Response

The importance of plant small heat shock proteins (sHsp) in multiple cellular processes has been evidenced by their unusual abundance and diversity; however, little is known about their biological role. Here, we characterized the in vitro chaperone activity and subcellular localization of nodulin 22 of Phaseolus vulgaris (PvNod22; common bean) and explored its cellular function through a virus-induced gene silencing–based reverse genetics approach. We established that PvNod22 facilitated the refolding of a model substrate in vitro, suggesting that it acts as a molecular chaperone in the cell. Through microscopy analyses of PvNod22, we determined its localization in the endoplasmic reticulum (ER). Furthermore, we found that silencing of PvNod22 resulted in necrotic lesions in the aerial organs of P. vulgaris plants cultivated under optimal conditions and that downregulation of PvNod22 activated the ER-unfolded protein response (UPR) and cell death. We also established that PvNod22 expression in wild-type bean plants was modulated by abiotic stress but not by chemicals that trigger the UPR, indicating PvNod22 is not under UPR control. Our results suggest that the ability of PvNod22 to suppress protein aggregation contributes to the maintenance of ER homeostasis, thus preventing the induction of cell death via UPR in response to oxidative stress during plant-microbe interactions.

scholarly journals Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic β-cells under glucolipotoxic stress

2019 ◽  
Author(s):  
Sarah A. White ◽  
Lisa Zhang ◽  
Yu Hsuan Carol Yang ◽  
Dan S. Luciani
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Unfolded Protein ◽  
Protein Response

ABSTRACTER stress and apoptosis contribute to the loss of pancreatic β-cells under the pro-diabetic conditions of glucolipotoxicity. Although activation of the canonical pathway of intrinsic apoptosis is known to require Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death have not been demonstrated. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro happens in sequential stages; first via non-apoptotic mechanisms and later by apoptosis, which Bax and Bak were redundant in triggering. In contrast, they had non-redundant roles in mediating staurosporine-induced β-cell apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that Bax and Bak together dampen the unfolded protein response in β-cells during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings identify novel roles of the canonical apoptosis machinery in modulating stress signals that are important for the pathobiology of β-cells in diabetes.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

Relevance of mitochondrial dysfunction during Sorafenib-induced cell death in liver cancer cells. Role of oxidative and nitrogen reactive species

2021 ◽  
Vol 165 ◽  
pp. 54
Author(s):  
Patricia de la Cruz-Ojeda ◽  
M. Ángeles Rodríguez-Hernández ◽  
Elena Navarro-Villarán ◽  
Paloma Gallego ◽  
Pavla Staňková ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Reactive Species ◽  
Liver Cancer Cells ◽  
Nitrogen Reactive Species

scholarly journals The Effects of Bergamot Polyphenolic Fraction, Cynara cardunculus, and Olea europea L. Extract on Doxorubicin-Induced Cardiotoxicity

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2158
Author(s):  
Jessica Maiuolo ◽  
Irene Bava ◽  
Cristina Carresi ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apoptotic Cell ◽  
Natural Compounds ◽  
Cynara Cardunculus ◽  
Unfolded Protein ◽  
Wide Range ◽  
Vitro Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Doxorubicin is an anthracycline that is commonly used as a chemotherapy drug due to its cytotoxic effects. The clinical use of doxorubicin is limited due to its known cardiotoxic effects. Treatment with anthracyclines causes heart failure in 15–17% of patients, resulting in mitochondrial dysfunction, the accumulation of reactive oxygen species, intracellular calcium dysregulation, the deterioration of the cardiomyocyte structure, and apoptotic cell death. Polyphenols have a wide range of beneficial properties, and particular importance is given to Bergamot Polyphenolic Fraction; Oleuropein, one of the main polyphenolic compounds of olive oil; and Cynara cardunculus extract. These natural compounds have particular beneficial characteristics, owing to their high polyphenol contents. Among these, their antioxidant and antoproliferative properties are the most important. The aim of this paper was to investigate the effects of these three plant derivatives using an in vitro model of cardiotoxicity induced by the treatment of rat embryonic cardiomyoblasts (H9c2) with doxorubicin. The biological mechanisms involved and the crosstalk existing between the mitochondria and the endoplasmic reticulum were examined. Bergamot Polyphenolic Fraction, Oleuropein, and Cynara cardunculus extract were able to decrease the damage induced by exposure to doxorubicin. In particular, these natural compounds were found to reduce cell mortality and oxidative damage, increase the lipid content, and decrease the concentration of calcium ions that escaped from the endoplasmic reticulum. In addition, the direct involvement of this cellular organelle was demonstrated by silencing the ATF6 arm of the Unfolded Protein Response, which was activated after treatment with doxorubicin.

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