Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells

Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.

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Palmitate Causes Endoplasmic Reticulum Stress and Apoptosis in Human Mesenchymal Stem Cells: Prevention by AMPK Activator

Endocrinology ◽

10.1210/en.2012-1418 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5275-5284 ◽

Cited By ~ 41

Author(s):

Jun Lu ◽

Qinghua Wang ◽

Lianghu Huang ◽

Huiyue Dong ◽

Lingjing Lin ◽

...

Keyword(s):

Stem Cells ◽

Endoplasmic Reticulum ◽

Mesenchymal Stem Cells ◽

Protein Kinase ◽

Er Stress ◽

Human Mesenchymal Stem Cells ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Human Umbilical Cord ◽

Amp Activated Protein Kinase

Abstract Elevated circulating saturated fatty acids concentration is commonly associated with poorly controlled diabetes. The highly prevalent free fatty acid palmitate could induce apoptosis in various cell types, but little is known about its effects on human mesenchymal stem cells (MSCs). Here, we report that prolonged exposure to palmitate induces human bone marrow-derived MSC (hBM-MSC) and human umbilical cord-derived MSC apoptosis. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cell apoptosis. Palmitate activated XBP1 splicing, elF2α (eukaryotic translation initiation factor 2α) phosphorylation, and CHOP, ATF4, BiP, and GRP94 transcription in hBM-MSCs. ERK1/2 and p38 MAPK phosphorylation were also induced by palmitate in hBM-MSCs. A selective p38 inhibitor inhibited palmitate activation of the ER stress, whereas the ERK1/2 inhibitors had no effect. The AMP-activated protein kinase activator aminoimidazole carboxamide ribonucleotide blocked palmitate-induced ER stress and apoptosis. These findings suggest that palmitate induces ER stress and ERK1/2 and p38 activation in hBM-MSCs, and AMP-activated protein kinase activator prevents the deleterious effects of palmitate by inhibiting ER stress and apoptosis.

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P0015SIRT2 REGULATES CISPLATIN-INDUCED ENDOPLASMIC RETICULUM STRESS THROUGH HEAT SHOCK FACTOR 1 DEACETYLATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0015 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Woong Park ◽

Hyeongwan Kim ◽

Yujin Jung ◽

Kyung Pyo Kang ◽

Won Kim

Keyword(s):

Endoplasmic Reticulum ◽

Heat Shock ◽

Er Stress ◽

Knockout Mice ◽

Malignant Tumors ◽

Heat Shock Factor ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Heat Shock Factor 1 ◽

Caspase 12

Abstract Background and Aims Nephrotoxicity is an important cisplatin-induced adverse reaction and restricts the use of cisplatin to treat malignant tumors. Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded proteins, and is induced by cisplatin in kidneys. SIRT2 nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase is a member of the sirtuin family, but its role in cisplatin-induced ER stress remains unclear. Method To investigate the effect of SIRT2 on cisplatin-induced ER stress using SIRT2 knockout mice and human proximal tubular epithelial cells (HK-2 cells). We treated cisplatin (20 µg/mL) or induced by intraperitoneal injection of cisplatin (20 mg/kg) and evaluated the changes of ER stress and its signal mechanism. Results Cisplatin administration was found to significantly increase the expressions of PRKR-like ER kinase (PERK), phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and the C/EBP homologous protein (CHOP) and caspase-12 in the kidneys of SIRT2-wild type mice. However, cisplatin-induced increases in the expressions of p-PERK, p-eIF2α, CHOP and, caspase-12 were diminished in kidneys of SIRT2 knockout mice. In vitro, cisplatin significantly increased the expressions of p-PERK, p-eIF2α, CHOP, and caspase-12 in HK-2 cells. When the effect of SIRT2 on cisplatin-induced ER stress was evaluated using SIRT2-siRNA (ON-TARGET plus human SIRT2 siRNA) or the SIRT2 inhibitors, AGK2 and AK1, knockdown or inhibition of SIRT2 significantly attenuated the cisplatin-induced protein expression of p-PERK, p-eIF2α, CHOP, and caspase-12. Immunoprecipitation studies showed SIRT2 bound physically to heat shock factor (HSF)1 and that HSF1 acetylation was significantly increased by cisplatin. In addition, knockdown of SIRT2 increased cisplatin-induced HSF1 acetylation and increased the expression of heat shock protein (HSP)70. Conclusion These observations suggest that suppression of SIRT2 ameliorates cisplatin-induced ER stress by increasing HSF1 acetylation and HSP expression.

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Aquaporin-11 Contributes to TGF-β1-induced Endoplasmic Reticulum Stress in Human Visceral Adipocytes: Role in Obesity-Associated Inflammation

Cells ◽

10.3390/cells9061403 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1403 ◽

Cited By ~ 1

Author(s):

Gema Frühbeck ◽

Inmaculada Balaguer ◽

Leire Méndez-Giménez ◽

Víctor Valentí ◽

Sara Becerril ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Er Stress ◽

Subcutaneous Fat ◽

Subcellular Fractionation ◽

Normal Weight ◽

Compensatory Mechanism ◽

Tissue Samples ◽

Water Glycerol ◽

Tgf Β1

Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-α, and particularly TGF-β1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-β1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-β1-induced ER stress in visceral adipocytes. Owing to its “peroxiporin” properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.

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Oxidative Damage to the Endoplasmic Reticulum is Implicated in Ischemic Neuronal Cell Death

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000089600.87125.ad ◽

2003 ◽

Vol 23 (10) ◽

pp. 1117-1128 ◽

Cited By ~ 88

Author(s):

Takeshi Hayashi ◽

Atsushi Saito ◽

Shuzo Okuno ◽

Michel Ferrand-Drake ◽

Robert L Dodd ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Protein Modification ◽

Neuronal Degeneration ◽

Neuronal Damage ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Transgenic Animals ◽

Initiation Factor

The endoplasmic reticulum (ER), which plays important roles in apoptosis, is susceptible to oxidative stress. Because reactive oxygen species (ROS) are robustly produced in the ischemic brain, ER damage by ROS may be implicated in ischemic neuronal cell death. We induced global brain ischemia on wild-type and copper/zinc superoxide dismutase (SOD1) transgenic rats and compared ER stress and neuronal damage. Phosphorylated forms of eukaryotic initiation factor 2α (eIF2α) and RNA-dependent protein kinase-like ER eIF2α kinase (PERK), both of which play active roles in apoptosis, were increased in hippocampal CA1 neurons after ischemia but to a lesser degree in the transgenic animals. This finding, together with the finding that the transgenic animals showed decreased neuronal degeneration, indicates that oxidative ER damage is involved in ischemic neuronal cell death. To elucidate the mechanisms of ER damage by ROS, we analyzed glucose-regulated protein 78 (GRP78) binding with PERK and oxidative ER protein modification. The proteins were oxidatively modified and stagnated in the ER lumen, and GRP78 was detached from PERK by ischemia, all of which were attenuated by SOD1 overexpression. We propose that ROS attack and modify ER proteins and elicit ER stress response, which results in neuronal cell death.

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Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

Journal of Virology ◽

10.1128/jvi.02307-08 ◽

2009 ◽

Vol 83 (8) ◽

pp. 3463-3474 ◽

Cited By ~ 90

Author(s):

Baoqin Xuan ◽

Zhikang Qian ◽

Emi Torigoi ◽

Dong Yu

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Human Cytomegalovirus ◽

Initiation Factor ◽

Α Subunit ◽

Unfolded Protein ◽

Initiation Factor 2 ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

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APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

Bioscience Reports ◽

10.1042/bsr20171713 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 13

Author(s):

Hongxiu Wen ◽

Vinod Kumar ◽

Xiqian Lan ◽

Seyedeh Shadafarin Marashi Shoshtari ◽

Judith M. Eng ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Kidney Diseases ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Wild Type ◽

Eukaryotic Translation ◽

Risk Variants ◽

Eukaryotic Translation Initiation ◽

Underlying Mechanisms

Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.

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Eukaryotic translation initiation factor 2A protects pancreatic beta cells during endoplasmic reticulum stress while rescuing translation inhibition

10.21203/rs.3.rs-343655/v1 ◽

2021 ◽

Author(s):

Evgeniy Panzhinskiy ◽

Søs Skovsø ◽

Haoning Cen ◽

Kwan Chu ◽

Kate MacDonald ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Protein Translation ◽

Human Islets ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Related Factor ◽

Min6 Cells ◽

Primary Mouse ◽

Mouse Islets

Abstract The endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) helps decide cell survival in diabetes. The alternative eukaryotic initiation factor 2A (EIF2A) has been proposed to mediate EIF2S1-independent translation during cellular stress and viral infection, but its role in cells is unknown. EIF2A abundance is high in human and mouse islets relative to other tissues, and both thapsigargin and palmitate significantly increased EIF2A mRNA and EIF2A protein levels in MIN6 cells, mouse islets and human islets. Knockdowns of EIF2A, the related factor EIF2D, or both EIF2A and EIF2D, were not sufficient to cause apoptosis. On the other hand, transient or stable EIF2A over-expression protected MIN6 cells, primary mouse islets, and human islets from ER stress-induced, caspase-3-dependent apoptosis. Mechanistically, EIF2A overexpression decreased ERN1 (also known as IRE1) expression in thapsigargin-treated MIN6 cells or human islets. In vivo, cell specific EIF2A viral overexpression reduced ER stress, improved insulin secretion, and abrogated hyperglycemia in Ins2Akita/WT mice. EIF2A overexpression significantly increased expression of genes involved in protein translation and reduced expression of pro-apoptotic genes (e.g. ALDH1A3). Remarkably, the decrease in global protein synthesis during UPR was prevented by EIF2A, despite ER stress-induced EIF2S1 phosphorylation. The protective effects of EIF2A were additive to those of ISRIB, a drug that counteracts the effects of EIF2S1 phosphorylation. Cells overexpressing EIF2A showed higher expression of translation factor EIF2B5, which may contribute to the lack of translational inhibition in these cells. We conclude that EIF2A is a novel target for cell protection and the circumvention of EIF2S1-mediated translational repression.

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Chloroquine induces apoptosis in pancreatic neuroendocrine neoplasms via endoplasmic reticulum stress

Endocrine Related Cancer ◽

10.1530/erc-20-0028 ◽

2020 ◽

Vol 27 (7) ◽

pp. 431-439

Author(s):

Kenzo Nakano ◽

Toshihiko Masui ◽

Akitada Yogo ◽

Yuichiro Uchida ◽

Asahi Sato ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Lines ◽

Apoptotic Cell ◽

Tumour Size ◽

Neuroendocrine Neoplasms ◽

Low Grade ◽

Pancreatic Neuroendocrine Neoplasms ◽

Dismal Prognosis ◽

Well Differentiated

Although pancreatic neuroendocrine neoplasms (PanNENs) are generally indolent, patients with distant metastasis have a dismal prognosis. Recently, the autophagy inhibitor chloroquine (CQ) has been shown to suppress the tumour growth of PanNENs, but the detailed mechanisms have not been elucidated. Furthermore, these results were obtained from poorly differentiated cell lines rather than well-differentiated cell lines, which is the most prevalent type in this tumour. To explore the mechanism and efficacy of CQ on PanNENs, we applied CQ to cell lines and evaluated the resulting apoptosis and endoplasmic reticulum (ER) stress. CQ treatment induced ER stress, and an unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway, resulting in the expression of the pro-apoptotic protein C/EBP homologous protein (CHOP), which reflects ER-stress-mediated apoptotic cell death. Furthermore, hydroxychloroquine (HCQ) was effective in Men1 heterozygous-deficient (Men1+/ΔN3-8) mice, a mouse PanNEN model that is considered to correspond to human low-grade PanNEN. HCQ administration decreased tumour size in Men1+/ΔN3-8 mice. In the HCQ group, histological analyses revealed that proliferative activity was unchanged, but apoptosis was accelerated, accompanied by CHOP expression. These results suggest that autophagy inhibition by CQ/HCQ could be used for the treatment of PanNEN, including the well-differentiated type.

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A novel secretagogin/ATF4 pathway is involved in oxidized LDL-induced endoplasmic reticulum stress and islet β-cell apoptosis

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa142 ◽

2020 ◽

Author(s):

Li Wu ◽

Yuncheng Lv ◽

Ying Lv ◽

Sunmin Xiang ◽

Zhibo Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Er Stress ◽

Cell Apoptosis ◽

Initiation Factor ◽

Β Cells ◽

Β Cell ◽

Immunoprecipitation Assay ◽

Min6 Cells ◽

Stress Markers

Abstract Excessive accumulation of cholesterol in β cells initiates endoplasmic reticulum (ER) stress and associated apoptosis. We have reported that excessive uptake of cholesterol by MIN6 cells decreases the expression of secretagogin (SCGN) and then attenuates insulin secretion. Here, we aimed to determine whether cholesterol-induced SCGN decrease is involved in the modulation of ER stress and apoptosis in pancreatic β cells. In this study, MIN6 cells were treated with oxidized low-density lipoprotein (ox-LDL) for 24 h, and then intracellular lipid droplets and cell apoptosis were quantified, and SCGN and ER stress markers were identified by western blot analysis. Furthermore, small interfer RNA (siRNA)-mediated SCGN knockdown and recombinant plasmid-mediated SCGN restoration experiments were performed to confirm the role of SCGN in ER stress and associated cell apoptosis. Finally, the interaction of SCGN with ATF4 was computationally predicted and then validated by a co-immunoprecipitation assay. We found that ox-LDL treatment increased the levels of ER stress markers, such as phosphorylated protein kinase-like endoplasmic reticulum kinase, phosphorylated eukaryotic initiation factor 2 alpha, activating transcription factor 4 (ATF4), and transcription factor CCAAT-enhancer-binding protein homologous protein, and promoted MIN6 cell apoptosis; in addition, the expression of SCGN was downregulated. siRNA-mediated SCGN knockdown exacerbated β-cell ER stress by increasing ATF4 expression. Pretreatment of MIN6 cells with the recombinant SCGN partly antagonized ox-LDL-induced ER stress and apoptosis. Furthermore, a co-immunoprecipitation assay revealed an interaction between SCGN and ATF4 in MIN6 cells. Taken together, these results demonstrated that pancreatic β-cell apoptosis induced by ox-LDL treatment can be attributed, in part, to an SCGN/ATF4-dependent ER stress response.

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Impact of endoplasmic reticulum stress on oocyte aging mechanisms

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa040 ◽

2020 ◽

Vol 26 (8) ◽

pp. 567-575

Author(s):

Isao Takehara ◽

Hideki Igarashi ◽

Jun Kawagoe ◽

Koki Matsuo ◽

Kyoko Takahashi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Embryo Development ◽

Oocyte Quality ◽

Initiation Factor ◽

Aged Mouse ◽

Age Related ◽

Initiation Factor 2 ◽

Aging Mechanisms

Abstract Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as ‘fresh’ and ‘aged’, respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and ATF6 pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

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