scholarly journals Neutrophils drive endoplasmic reticulum stress-mediated apoptosis in cancer cells through arginase-1 release

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rósula García-Navas ◽  
Consuelo Gajate ◽  
Faustino Mollinedo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antitumor Action ◽  
Human Neutrophils ◽  
Pancreatic Cancer Cells ◽  
Arginase 1 ◽  
Apoptosis In Cancer Cells

AbstractHuman neutrophils constitutively express high amounts of arginase-1, which depletes arginine from the surrounding medium and downregulates T-cell activation. Here, we have found that neutrophil arginase-1, released from activated human neutrophils or dead cells, induced apoptosis in cancer cells through an endoplasmic reticulum (ER) stress pathway. Silencing of PERK in cancer cells prevented the induction of ER stress and apoptosis. Arginase inhibitor Nω-hydroxy-nor-arginine inhibited apoptosis and ER stress response induced by conditioned medium from activated neutrophils. A number of tumor cell lines, derived from different tissues, were sensitive to neutrophil arginase-1, with pancreatic, breast, ovarian and lung cancer cells showing the highest sensitivity. Neutrophil-released arginase-1 and arginine deprivation potentiated the antitumor action against pancreatic cancer cells of the ER-targeted antitumor alkylphospholipid analog edelfosine. Our study demonstrates the involvement of neutrophil arginase-1 in cancer cell killing and highlights the importance and complex role of neutrophils in tumor surveillance and biology.

scholarly journals Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4173
Author(s):  
Faustino Mollinedo ◽  
Consuelo Gajate
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Ether Lipid ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

scholarly journals Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells

2005 ◽  
Vol 65 (24) ◽  
pp. 11510-11519 ◽  
Author(s):  
Steffan T. Nawrocki ◽  
Jennifer S. Carew ◽  
Kenneth Dunner ◽  
Lawrence H. Boise ◽  
Paul J. Chiao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals Induction of Endoplasmic Reticulum-induced Stress Genes in Panc-1 Pancreatic Cancer Cells Is Dependent on Sp Proteins

2005 ◽  
Vol 280 (16) ◽  
pp. 16508-16513 ◽  
Author(s):  
Maen Abdelrahim ◽  
Shengxi Liu ◽  
Stephen Safe
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Gene Promoters ◽  
Er Stress Response ◽  
Pancreatic Cancer Cells ◽  
Pharmacologically Active

Endoplasmic reticulum (ER) stress plays a critical role in multiple diseases, and pharmacologically active drugs can induce cell death through ER stress pathways. Stress-induced genes are activated through assembly of transcription factors on ER stress response elements (ERSEs) in target gene promoters. Gel mobility shift and chromatin immunoprecipitation assays have confirmed interactions of NF-Y and YY1 with the distal motifs of the tripartite ERSE from the glucose-related protein 78 (GRP78) gene promoter. The GC-rich nonanucleotide (N9) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins. Sp proteins are constitutively bound to the ERSE; however, activation of GRP78 protein (or reporter gene) by thapsigargin or tunicamycin is inhibited after cotransfection with small inhibitory RNAs for Sp1, Sp3, and Sp4. This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs.

scholarly journals Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Changhong Li ◽  
Kui Zhang ◽  
Guangzhao Pan ◽  
Haoyan Ji ◽  
Chongyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Growth ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Xenograft ◽  
Anticancer Activities ◽  
Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

scholarly journals ER stress compromises VEGFA secretion of pancreatic cancer cells under hypoxic conditions, thereby contributing to tumor hypoxia

HPB ◽  
2016 ◽  
Vol 18 ◽  
pp. e837
Author(s):  
B. Kong ◽  
T. Cheng ◽  
I. Regel ◽  
S. Raulefs ◽  
H. Friess ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Hypoxia ◽  
Hypoxic Conditions ◽  
Pancreatic Cancer Cells

Abstract 442: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation in Angiotensin II (Ang-II)-dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Heinrich E Lob ◽  
Jiunn Song ◽  
Scott D Butler ◽  
Allyn L Mark ◽  
Robin L Davisson
Keyword(s):  
T Cell ◽  
Er Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Fold Increase ◽  
Peripheral Inflammation ◽  
Ang Ii ◽  
Peripheral Vascular ◽  
Control Virus

The SFO is implicated in peripheral T cell activation and the genesis of Ang-II-dependent hypertension. Our recent studies show that ER stress in the SFO is also a key mechanism underlying the development of Ang-II hypertension. Because the ER is closely integrated with initiation of the adaptive immune response, we hypothesized that ER stress in the SFO contributes to peripheral inflammation in Ang-II hypertension. First, 5 days of intracerebroventricular (ICV) infusion of thapsigargin (Tg, 1 ug/day), a chemical ER stress inducer, caused a significant increase in CD3 + T cells in aortas (Tg: 11.9 ± 3.5 x 10 3 cells/aorta vs. Vehicle: 2.2 ± 0.7 x 10 3 cells/aorta , n = 6, p<0.05) and blood (Tg: 9.9 ± 1.8 x 10 4 cells/ mL vs. Vehicle: 2.9 ± 0.6 x 10 4 cells/ mL, n = 6, p<0.05). Furthermore, quantitative real-time PCR of SFO micropunches showed a 15-fold increase of TNF-α, a pro-inflammatory cytokine, a 3-fold increase of CCL5, a T cell attracting chemokine and a 3-fold increase in CD3, a T cell marker, (n = 4, p<0.05). To test the functional role of ER stress in the SFO in peripheral T cell activation, we targeted an adenovirus encoding GRP78 (AdGRP78), a molecular ER stress inhibitor, to this brain region during chronic systemic Ang-II infusion (600 ng/kg/min, 14 days). Our results demonstrate a significant reduction in T cell accumulation in aortas compared to control virus (AdLacZ) treatment (AdGRP78: 0.5 ± 0.07 x 10 4 cells/aorta vs. AdLacZ: 8.7 ± 2.1 x 10 4 cells/aorta, n = 6, p<0.05). These data show that 1) brain ER stress induces inflammation in the SFO and peripheral vascular T cell activation, and 2) ER stress in the SFO is linked to peripheral vascular T cell activation in Ang-II-dependent hypertension. These results suggest that ER stress and inflammation in the SFO induce peripheral vascular T cell activation and inflammation in Ang-II hypertension.

scholarly journals Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function

2017 ◽  
Vol 5 (8) ◽  
pp. 666-675 ◽  
Author(s):  
Jessica E. Thaxton ◽  
Caroline Wallace ◽  
Brian Riesenberg ◽  
Yongliang Zhang ◽  
Chrystal M. Paulos ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
Endoplasmic Reticulum Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell

Generation of endoplasmic reticulum stress and inhibition of autophagy by plitidepsin induces proteotoxic apoptosis in cancer cells

2020 ◽  
Vol 172 ◽  
pp. 113744 ◽  
Author(s):  
Alejandro Losada ◽  
Juan José Berlanga ◽  
José Manuel Molina-Guijarro ◽  
Antonio Jiménez-Ruiz ◽  
Federico Gago ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cancer Cells ◽  
Apoptosis In Cancer Cells

scholarly journals High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

2017 ◽  
Vol 95 (2) ◽  
pp. 289-294 ◽  
Author(s):  
Ali Burak Ozkaya ◽  
Handan Ak ◽  
Hikmet Hakan Aydin
Keyword(s):  
Breast Cancer ◽  
Vitamin D ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Survival Function ◽  
Active Form ◽  
Breast Cancer Cell Lines ◽  
Transcriptomic Profile

Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis as well as the inhibition of angiogenesis and metastasis. Understanding the mechanisms of action for calcitriol will help with the development of novel treatment strategies. Since vitamin D exerts its cellular actions via binding to its receptor and by altering expressions of a set of genes, we aimed to evaluate the effect of calcitriol on transcriptomic profile of breast cancer cells. We previously demonstrated that calcitriol alters endoplasmic reticulum (ER) stress markers, therefore in this study we have focused on ER-stress-related genes to reveal calcitriols action on these genes in particular. We have treated breast cancer cell lines MCF-7 and MDA-MB-231 with previously determined IC50 concentrations of calcitriol and evaluated the transcriptomic alterations via microarray. During analysis, only genes altered by at least 2-fold with a P value < 0.05 were taken into consideration. Our findings revealed an ER-stress-associated transcriptomic profile induced by calcitriol. Induced genes include genes with a pro-survival function (NUPR1, DNAJB9, HMOX1, LCN2, and LAMP3) and with a pro-death function (CHOP (DDIT3), DDIT4, NDGR1, NOXA, and CLGN). These results suggest that calcitriol induces an ER-stress-like response inducing both pro-survival and pro-death transcripts in the process.

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