scholarly journals Polyphenol-rich extract induces apoptosis with immunogenic markers in melanoma cells through the ER stress-associated kinase PERK

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Karol Prieto ◽  
Yu Cao ◽  
Eslam Mohamed ◽  
Jimena Trillo-Tinoco ◽  
Rosa A. Sierra ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Calcium Release ◽  
Melanoma Cells ◽  
Melanoma Tumor ◽  
Cancer Cell Death ◽  
Extracellular Release ◽  
Induced Apoptosis ◽  
Stress Mediators

Abstract Polyphenols elicit antitumor activities, in part, through the induction of anti- or pro-oxidant effects in cancer cells which promote priming of protective anti-tumor immunity. We recently characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) that stimulates in vivo antitumor responses against breast and melanoma tumor models via the promotion of immunogenic cancer cell death (ICD). However, the primary mediators whereby P2Et promotes ICD remained unknown. Here, we sought to elucidate the role that severe endoplasmic reticulum (ER) stress plays in mediating P2Et-induced apoptosis and ICD in murine melanoma cells. Our findings demonstrate a substantial selective induction of specific ER-stress mediators in B16-F10 melanoma cells treated with P2Et. While knockout of the ER stress-associated PKR-like ER kinase (PERK) prevented induction of apoptosis and expression of ICD markers in P2Et-treated cells, deletion of X-box binding protein 1 (Xbp1) did not. P2Et-driven activation of PERK in melanoma cells was found to promote ER-calcium release, disrupt mitochondrial membrane potential, and trigger upregulation of ICD drivers, surface calreticulin expression, and extracellular release of ATP and HMGB1. Notably, calcium release inhibition, but not targeting of PERK-driven integrated stress responses, prevented P2Et-induced apoptosis. Collectively, these results underline the central role of PERK-directed calcium release in mediating the antitumor and immunogenic actions of P2Et in melanoma cells.

scholarly journals Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

2009 ◽  
Vol 186 (6) ◽  
pp. 783-792 ◽  
Author(s):  
Gang Li ◽  
Marco Mongillo ◽  
King-Tung Chin ◽  
Heather Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Calcium Release ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Calcium Dependent ◽  
Insulin Resistant ◽  
Stressed Cells ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-α–IP3R pathway.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

scholarly journals Synergistic Effect Induced by Gold Nanoparticles with Polyphenols Shell during Thermal Therapy: Macrophage Inflammatory Response and Cancer Cell Death Assessment

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3610
Author(s):  
Valeria De Matteis ◽  
Mariafrancesca Cascione ◽  
Loris Rizzello ◽  
Daniela Erminia Manno ◽  
Claudia Di Guglielmo ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Calcium Release ◽  
Chemical Properties ◽  
Chemical Route ◽  
Au Nps ◽  
Anticancer Properties ◽  
Cancer Cell Death ◽  
Combined Strategy

Background: In recent decades, gold nanoparticle (Au NP)-based cancer therapy has been heavily debated. The physico-chemical properties of AuNPs can be exploited in photothermal therapy, making them a powerful tool for selectively killing cancer cells. However, the synthetic side products and capping agents often induce a strong activation of the inflammatory pathways of macrophages, thus limiting their further applications in vivo. Methods: Here, we described a green method to obtain stable polyphenol-capped AuNPs (Au NPs@polyphenols), as polyphenols are known for their anti-inflammatory and anticancer properties. These NPs were used in human macrophages to test key inflammation-related markers, such as NF-κB, TNF-α, and interleukins-6 and 8. The results were compared with similar NPs obtained by a traditional chemical route (without the polyphenol coating), proving the potential of Au NPs@polyphenols to strongly promote the shutdown of inflammation. This was useful in developing them for use as heat-synergized tools in the thermal treatment of two types of cancer cells, namely, breast cancer (MCF-7) and neuroblastoma (SH-SY5Y) cells. The cell viability, calcium release, oxidative stress, HSP-70 expression, mitochondrial, and DNA damage, as well as cytoskeleton alteration, were evaluated. Results: Our results clearly demonstrate that the combined strategy markedly exerts anticancer effects against the tested cancer cell, while neither of the single treatments (only heat or only NPs) induced significant changes. Conclusions: Au NP@polyphenols may be powerful agents in cancer treatment.

scholarly journals The Induction of Apoptosis in A375 Malignant Melanoma Cells bySutherlandia frutescens

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Nicola B. van der Walt ◽  
Zahra Zakeri ◽  
Marianne J. Cronjé
Keyword(s):  
Malignant Melanoma ◽  
Basic Mechanism ◽  
Melanoma Cells ◽  
Caspase Activation ◽  
Nuclear Condensation ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor ◽  
A375 Melanoma Cell Line ◽  
A375 Cells

Sutherlandia frutescensis a medicinal plant indigenous to Southern Africa and is commonly known as the “cancer bush.” This plant has traditionally been used for the treatment of various ailments, although it is best known for its claims of activity against “internal” cancers. Here we report on its effect on melanoma cells. The aim of this study was to investigate whether an extract ofS. frutescenscould induce apoptosis in the A375 melanoma cell line and to outline the basic mechanism of action.S. frutescensextract induced apoptosis in A375 cells as evidenced by morphological features of apoptosis, phosphatidylserine exposure, nuclear condensation, caspase activation, and the release of cytochromecfrom the mitochondria. Studies in the presence of a pan-caspase inhibitor allude to caspase-independent cell death, which appeared to be mediated by the apoptosis inducing factor. Taken together, the results of this study show thatS. frutescensextract is effective in inducing apoptosis in malignant melanoma cells and indicates that furtherin vivomechanistic studies may be warranted.

scholarly journals Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Deepika Vasudevan ◽  
Sarah D. Neuman ◽  
Amy Yang ◽  
Lea Lough ◽  
Brian Brown ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Rna Binding ◽  
Open Reading Frames ◽  
Binding Motif ◽  
Integrated Stress Response ◽  
Developmental Defects ◽  
Initiation Factors

Abstract The Integrated Stress Response (ISR) helps metazoan cells adapt to cellular stress by limiting the availability of initiator methionyl-tRNA for translation. Such limiting conditions paradoxically stimulate the translation of ATF4 mRNA through a regulatory 5′ leader sequence with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expression. Here, we report the identification of two critical regulators of such ATF4 induction, the noncanonical initiation factors eIF2D and DENR. Loss of eIF2D and DENR in Drosophila results in increased vulnerability to amino acid deprivation, susceptibility to retinal degeneration caused by endoplasmic reticulum (ER) stress, and developmental defects similar to ATF4 mutants. eIF2D requires its RNA-binding motif for regulation of 5′ leader-mediated ATF4 translation. Consistently, eIF2D and DENR deficient human cells show impaired ATF4 protein induction in response to ER stress. Altogether, our findings indicate that eIF2D and DENR are critical mediators of ATF4 translational induction and stress responses in vivo.

scholarly journals N6-(2-hydroxyethyl)-Adenosine Induces Apoptosis via ER Stress and Autophagy of Gastric Carcinoma Cells In Vitro and In Vivo

2020 ◽  
Vol 21 (16) ◽  
pp. 5815
Author(s):  
Hongqing Xie ◽  
Xiaotong Li ◽  
Weiwei Yang ◽  
Liping Yu ◽  
Xiasen Jiang ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Er Stress ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Antineoplastic Effect ◽  
Tumor Tissues ◽  
Induced Apoptosis ◽  
Species Production

Gastric cancer is the most common malignant tumor of the digestive tract and is great challenge in clinical treatment. N6-(2-Hydroxyethyl)-adenosine (HEA), widely present in various fungi, is a natural adenosine derivative with many biological and pharmacological activities. Here, we assessed the antineoplastic effect of HEA on gastric carcinoma. HEA exerted cytotoxic effects against gastric carcinoma cells (SGC-7901 and AGS) in a dose and time-dependent manner. Additionally, we found that HEA induced reactive oxygen species production and mitochondrial membrane potential depolarization. Moreover, it could trigger caspase-dependent apoptosis, promoting intracellular Ca2+-related endoplasmic reticulum (ER) stress and autophagy. On the other hand, HEA could significantly inhibit the growth of transplanted tumors in nude mice and induce apoptosis of tumor tissues cells in vivo. In conclusion, HEA induced apoptosis of gastric carcinoma cells in vitro and in vivo, demonstrating that HEA is a potential chemotherapeutic agent for gastric carcinoma.

scholarly journals Bosellia serrata-induced apoptosis is related with ER stress and calcium release

2007 ◽  
Vol 2 (4) ◽  
pp. 371-374 ◽  
Author(s):  
Hyung-Ryong Kim ◽  
Myung-Sunny Kim ◽  
Dae-Young Kwon ◽  
Soo-Wan Chae ◽  
Han-Jung Chae
Keyword(s):  
Er Stress ◽  
Calcium Release ◽  
Induced Apoptosis

scholarly journals Melanoma Addiction to GCDH is Mediated by NRF2 Tumor Suppressor Function

2021 ◽  
Author(s):  
Sachin Verma ◽  
David Crawford ◽  
Ali Khateb ◽  
Yongmei Feng ◽  
Eduard Sergienko ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Protein ◽  
Melanoma Cells ◽  
Binding Activity ◽  
Therapeutic Modality ◽  
Melanoma Tumor ◽  
Unfolded Protein ◽  
Dna Binding Activity ◽  
Lysine Catabolism

Tumor dependency on specific metabolic signals has guided numerous therapeutic approaches. Here we identify melanoma addiction to the mitochondrial protein Glutaryl-CoA dehydrogenase (GCDH), a component in lysine metabolism which controls protein glutarylation. GCDH knockdown promoted apoptotic Unfolded Protein Response signaling and cell death in melanoma cells, an activity blocked by knockdown of the upstream lysine catabolism enzyme DHTKD1. Correspondingly, reduced GCDH expression correlated with improved survival of melanoma patients. A key mediator of GCDH-dependent melanoma cell death programs is the transcription factor NRF2, which induces ATF3, CHOP, and CHAC1 transcription linking lysine catabolism with the UPR signaling. NRF2 glutarylation upon GCDH KD increased its stability and DNA binding activity, which coincided with increased transcriptional activity, promoting apoptotic UPR signaling and tumor suppression. In vivo, genetic GCDH inhibition effectively inhibited melanoma tumor growth. Overall, these findings demonstrate an addiction of melanoma cells to GCDH, which by controlling NRF2 glutarylation limits apoptotic UPR signaling. Inhibiting the GCDH pathway could represent a novel therapeutic modality to treat melanoma.

scholarly journals Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1742 ◽  
Author(s):  
Ching-Ying Huang ◽  
Jeng-Shyan Deng ◽  
Wen-Chin Huang ◽  
Wen-Ping Jiang ◽  
Guan-Jhong Huang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Er Stress ◽  
Anterior Segment ◽  
Signal Transduction Pathway ◽  
Lavage Fluid ◽  
Cell Number ◽  
Lps Challenge ◽  
Induced Apoptosis

The anti-inflammatory effect of hispolon has identified it as one of the most important compounds from Sanghuangporus sanghuang. The research objectives were to study this compound using an animal model by lipopolysaccharide (LPS)-induced acute lung injury. Hispolon treatment reduced the production of the pro-inflammatory mediator NO, TNF-α, IL-1β, and IL-6 induced by LPS challenge in the lung tissues, as well as decreasing their histological alterations and protein content. Total cell number was also reduced in the bronchoalveolar lavage fluid (BALF). Moreover, hispolon inhibited iNOS, COX-2 and IκB-α and phosphorylated IKK and MAPK, while increasing catalase, SOD, GPx, TLR4, AKT, HO-1, Nrf-2, Keap1 and PPARγ expression, after LPS challenge. It also regulated apoptosis, ER stress and the autophagy signal transduction pathway. The results of this study show that hispolon regulates LPS-induced ER stress (increasing CHOP, PERK, IRE1, ATF6 and GRP78 protein expression), apoptosis (decreasing caspase-3 and Bax and increasing Bcl-2 expression) and autophagy (reducing LC3 I/II and Beclin-1 expression). This in vivo experimental study suggests that hispolon suppresses the LPS-induced activation of inflammatory pathways, oxidative injury, ER stress, apoptosis and autophagy and has the potential to be used therapeutically in major anterior segment lung diseases.

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