p31 Deficiency Influences Endoplasmic Reticulum Tubular Morphology and Cell Survival

ABSTRACT p31, the mammalian orthologue of yeast Use1p, is an endoplasmic reticulum (ER)-localized soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) that forms a complex with other SNAREs, particularly syntaxin 18. However, the role of p31 in ER function remains unknown. To determine the role of p31 in vivo, we generated p31 conditional knockout mice. We found that homozygous deletion of the p31 gene led to early embryonic lethality before embryonic day 8.5. Conditional knockout of p31 in brains and mouse embryonic fibroblasts (MEFs) caused massive apoptosis accompanied by upregulation of ER stress-associated genes. Microscopic analysis showed vesiculation and subsequent enlargement of the ER membrane in p31-deficient cells. This type of drastic disorganization in the ER tubules has not been demonstrated to date. This marked change in ER structure preceded nuclear translocation of the ER stress-related transcription factor C/EBP homologous protein (CHOP), suggesting that ER stress-induced apoptosis resulted from disruption of the ER membrane structure. Taken together, these results suggest that p31 is an essential molecule involved in the maintenance of ER morphology and that its deficiency leads to ER stress-induced apoptosis.

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CARM1 Promotes Gastric Cancer Progression by Regulating TFE3 Mediated Autophagy Enhancement via Cytoplasmic AMPK-mTOR and Nuclear CARM1-TFE3 Signaling Pathways

10.21203/rs.3.rs-1088335/v1 ◽

2021 ◽

Author(s):

Suzhen Yang ◽

Jing Zhang ◽

Di Chen ◽

Jiayi Cao ◽

Ying Zheng ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Er Stress ◽

Signaling Pathways ◽

Nuclear Translocation ◽

Xenograft Model ◽

Induced Apoptosis

Abstract Background: The role of CARM1 in tumors is contradictory. It acts as an oncogene in most kinds of cancers while inhibits the progression of liver and pancreatic cancers. CARM1 has recently been reported to regulate autophagy, which is also context-dependent. However, the effect of CARM1 on gastric cancer has not been studied. We aimed to explore whether CARM1 was involved in the progression of gastric cancer by regulating autophagy.Methods: The clinical values of CARM1 and autophagy in gastric cancer were determined by immunohistochemistry and qRT-PCR. Transmission electron microscopy, immunofluorescence and western blotting were applied to recognize autophagy. The role of CARM1 in gastric cancer was investigated by CCK8, colony formation and flow cytometry assays in vitro and xenograft model in vivo. Immunoprecipitation assay was performed to illustrate the interaction of CARM1 and TFE3.Results: CARM1 was upregulated in clinical GC tissues and cell lines, and higher CARM1 expression predicted worse prognosis. CARM1 enhanced GC cell proliferation, facilitated G1-S transition and inhibited ER stress-induced apoptosis by regulating autophagy. Importantly, the treatment of CARM1 inhibitor rescued the tumor-promoting effects of CARM1 both in vitro and in vivo. Furthermore, we proved CARM1 heightened TFE3 nuclear translocation to induce autophagy via cytoplasmic AMPK-mTOR and nuclear CARM1-TFE3 signaling pathways.Conclusion: CARM1 promoted GC cell proliferation, accelerated G1-S transition and reduced ER stress-induced apoptosis by regulating autophagy. Mechanically, CARM1 triggered autophagy by facilitating TFE3 nuclear translocation via AMPK-mTOR and CARM1-TFE3 signaling pathways.

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Acetylsalicylic acid and salicylic acid present anticancer properties against melanoma by promoting nitric oxide-dependent endoplasmic reticulum stress and apoptosis

Scientific Reports ◽

10.1038/s41598-020-76824-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Priscila Ausina ◽

Jessica R. Branco ◽

Thainá M. Demaria ◽

Amanda M. Esteves ◽

João Gabriel B. Leandro ◽

...

Keyword(s):

Nitric Oxide ◽

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Acetylsalicylic Acid ◽

Er Stress ◽

In Vitro Models ◽

Anticancer Effects ◽

Factor C

AbstractMelanoma is the most aggressive and fatal type of skin cancer due to being highly proliferative. Acetylsalicylic acid (ASA; Aspirin) and salicylic acid (SA) are ancient drugs with multiple applications in medicine. Here, we showed that ASA and SA present anticancer effects against a murine model of implanted melanoma. These effects were also validated in 3D- and 2D-cultured melanoma B16F10 cells, where the drugs promoted pro-apoptotic effects. In both in vivo and in vitro models, SA and ASA triggered endoplasmic reticulum (ER) stress, which culminates with the upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). These effects are initiated by ASA/SA-triggered Akt/mTOR/AMPK-dependent activation of nitric oxide synthase 3 (eNOS), which increases nitric oxide and reactive oxygen species production inducing ER stress response. In the end, we propose that ASA and SA instigate anticancer effects by a novel mechanism, the activation of ER stress.

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Molecular Symbiosis of CHOP and C/EBPβ Isoform LIP Contributes to Endoplasmic Reticulum Stress-Induced Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.01507-09 ◽

2010 ◽

Vol 30 (14) ◽

pp. 3722-3731 ◽

Cited By ~ 73

Author(s):

Calin-Bogdan Chiribau ◽

Francesca Gaccioli ◽

Charlie C. Huang ◽

Celvie L. Yuan ◽

Maria Hatzoglou

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Er Stress ◽

Transcriptional Activation ◽

Nuclear Import ◽

Cellular Response ◽

Transcriptional Control ◽

Nuclear Translocation ◽

Basic Leucine Zipper ◽

Induced Apoptosis

ABSTRACT Induction of the transcription factor CHOP (CCAAT-binding homologous protein; GADD 153) is a critical cellular response for the transcriptional control of endoplasmic reticulum (ER) stress-induced apoptosis. Upon nuclear translocation, CHOP upregulates the transcription of proapoptotic factors and downregulates antiapoptotic genes. Transcriptional activation by CHOP involves heterodimerization with other members of the basic leucine zipper transcription factor (bZIP) family. We show that the bZIP protein C/EBPβ isoform LIP is required for nuclear translocation of CHOP during ER stress. In early ER stress, LIP undergoes proteasomal degradation in the cytoplasmic compartment. During later ER stress, LIP binds CHOP in both cytoplasmic and nuclear compartments and contributes to its nuclear import. By using CHOP-deficient cells and transfections of LIP-expressing vectors in C/EBPβ−/− mouse embryonic fibroblasts (MEFs), we show that the LIP-CHOP interaction has a stabilizing role for LIP. At the same time, CHOP uses LIP as a vehicle for nuclear import. LIP-expressing C/EBPβ−/− MEFs showed enhanced ER stress-induced apoptosis compared to C/EBPβ-null cells, a finding in agreement with the decreased levels of Bcl-2, a known transcriptional control target of CHOP. In view of the positive effect of CHOP-LIP interaction in mediating their proapoptotic functions, we propose this functional cooperativity as molecular symbiosis between proteins.

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

The Journal of Cell Biology ◽

10.1083/jcb.200904060 ◽

2009 ◽

Vol 186 (6) ◽

pp. 783-792 ◽

Cited By ~ 326

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.

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Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice

Bone ◽

10.1016/j.bone.2014.12.012 ◽

2015 ◽

Vol 73 ◽

pp. 60-68 ◽

Cited By ~ 67

Author(s):

Amy Y. Sato ◽

Xiaolin Tu ◽

Kevin A. McAndrews ◽

Lilian I. Plotkin ◽

Teresita Bellido

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Female Mice ◽

Induced Apoptosis

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Rapamycin Improves Palmitate-Induced ER Stress/NFκB Pathways Associated with Stimulating Autophagy in Adipocytes

Mediators of Inflammation ◽

10.1155/2015/272313 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Jiajing Yin ◽

Liping Gu ◽

Yufan Wang ◽

Nengguang Fan ◽

Yuhang Ma ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Nuclear Translocation ◽

Kinase Inhibitor ◽

Autophagy Flux ◽

Protein Levels ◽

Stress Effects ◽

Stress Markers

Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. Anin vitromodel was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2αphosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction.

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The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress

Blood ◽

10.1182/blood-2009-10-250423 ◽

2010 ◽

Vol 116 (18) ◽

pp. 3445-3455 ◽

Cited By ~ 27

Author(s):

Holger W. Auner ◽

Christine Beham-Schmid ◽

Niall Dillon ◽

Pierangela Sabbattini

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Caspase 3 ◽

Plasma Cells ◽

Myeloma Cell ◽

Immunoglobulin Secretion ◽

Effector Caspase ◽

Induced Apoptosis

Abstract Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress–induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.

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α-Mangostin Induces Apoptosis in Human Osteosarcoma Cells Through ROS-Mediated Endoplasmic Reticulum Stress via the WNT Pathway

Cell Transplantation ◽

10.1177/09636897211035080 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110350

Author(s):

Shengsen Yang ◽

Fei Zhou ◽

Yi Dong ◽

Fei Ren

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Caspase 3 ◽

Marker Proteins ◽

Human Osteosarcoma Cells ◽

Ros Accumulation ◽

Normal Human ◽

Induced Apoptosis ◽

Normal Human Osteoblast

α-mangostin has been confirmed to promote the apoptosis of MG-63 cells, but its specific pro-apoptosis mechanism in osteosarcoma (OS) remains further investigation. Here, we demonstrated that α-mangostin restrained the viability of OS cells (143B and Saos-2), but had little effect on the growth of normal human osteoblast. α-mangostin increased OS cell apoptosis by activating the caspase-3/8 cascade. Besides, α-mangostin induced endoplasmic reticulum (ER) stress and restrained the Wnt/β-catenin pathway activity. 4PBA (an ER stress inhibitor) or LiCl (an effective Wnt activator) treatment effectively hindered α-mangostin-induced apoptosis and the caspase-3/8 cascade. Furthermore, we also found that α-mangostin induced ER stress by promoting ROS production. And ER stress-mediated apoptosis caused by ROS accumulation depended on the inactivation of Wnt/β-catenin pathway. In addition, α-mangostin significantly hindered the growth of xenograft tumors, induced the expression of ER stress marker proteins and activation of the caspase-3/8 cascade, and restrained the Wnt/β-catenin signaling in vivo. In short, ROS-mediated ER stress was involved in α-mangostin triggered apoptosis, which might depended on Wnt/β-catenin signaling inactivation.

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Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

BMC Microbiology ◽

10.1186/s12866-021-02199-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Siqi Yuan ◽

Yao Fang ◽

Mengling Tang ◽

Zhiqiang Hu ◽

Chenglong Rao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Burkholderia Pseudomallei ◽

Treatment Strategies ◽

Effective Vaccine ◽

Tauroursodeoxycholic Acid ◽

Raw264.7 Macrophages ◽

Induced Apoptosis

Abstract Background Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. Results We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. Conclusion Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

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Gambogenic Acid Induces Endoplasmic Reticulum Stress in Colorectal Cancer via the Aurora A Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.736350 ◽

2021 ◽

Vol 9 ◽

Author(s):

Cheng Liu ◽

Jiaxin Xu ◽

Chenxu Guo ◽

Xugang Chen ◽

Chunmei Qian ◽

...

Keyword(s):

Colorectal Cancer ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Aurora A ◽

Eukaryotic Translation ◽

Induced Apoptosis

Colorectal cancer (CRC) is one of the most common malignancies in the world and has a poor prognosis. In the present research, gambogenic acid (GNA), isolated from the traditional Chinese medicine gamboge, markedly induced apoptosis and inhibited the proliferation of CRC in vitro and in vivo. Furthermore, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme (IRE) 1α and the eukaryotic translation initiation factor (eIF) 2α pathway. Pretreatment with salubrinal (an eIF2α inhibitor) rescued GNA-induced cell death. Furthermore, GNA downregulated the expression of Aurora A. The Aurora A inhibitor alisertib decreased ER stress. In human colorectal adenocarcinoma tissue, Aurora A was upregulated compared to normal colorectal epithelial nuclei. Furthermore, GNA ameliorated mouse colitis-associated cancer models. Our findings demonstrated that GNA significantly inhibited the proliferation of CRC through activation of ER stress by regulating Aurora A, which indicates the potential of GNA for preventing the progression of CRC.

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