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Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
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Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
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Osana S, Tsai CT, Suzuki N, Murayama K, Kaneko M, Hata K, Takada H, Kano Y, Nagatomi R. Inhibition of methionine aminopeptidase in C2C12 myoblasts disrupts cell integrity via increasing endoplasmic reticulum stress. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119901. [PMID: 39814187 DOI: 10.1016/j.bbamcr.2025.119901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/29/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025]
Abstract
Proteasome-dependent protein degradation and the digestion of peptides by aminopeptidases are essential for myogenesis. Methionine aminopeptidases (MetAPs) are uniquely involved in, both, the proteasomal degradation of proteins and in the regulation of translation (via involvement in post-translational modification). Suppressing MetAP1 and MetAP2 expression inhibits the myogenic differentiation of C2C12 myoblasts. However, the molecular mechanism by which inhibiting MetAPs impairs cellular function remains to be elucidated. Here, we provide evidence for our hypothesis that MetAPs regulate proteostasis and that their inhibition increases ER stress by disrupting the post-translational modification, and thereby compromises cell integrity. Thus, using C2C12 myoblasts, we investigate the effect of inhibiting MetAPs on cell proliferation and the molecular mechanisms underpinning its effects. We found that exposure to bengamide B (a MetAP inhibitor) caused C2C12 myoblasts to lose their proliferative abilities via cell cycle arrest. The underlying mechanism involved the accumulation of abnormal proteins (due to the decrease in the N-terminal methionine removal function) which led to increased endoplasmic reticulum stress, decreased protein synthesis, and a protective activation of the autophagy pathway. To identify the MetAP involved in these effects, we use siRNAs to specifically knockdown MetAP1 and MetAP2 expressions. We found that only MetAP2 knockdown mimicked the effects seen with bengamide B treatment. Thus, we suggest that MetAP2, rather than MetAP1, is involved in maintaining the integrity of C2C12 myoblasts. Our results are useful in understanding muscle regeneration, obesity, and overeating disorders. It will help guide new treatment strategies for these disorders.
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Affiliation(s)
- Shion Osana
- Department of Sports and Medical Science, Graduate School of Emergency Medical System, Kokushikan University, Tokyo 206-8515, Japan; Center for Neuroscience and Biomedical Engineering, University of Electro-Communications, Tokyo 182-8585, Japan.
| | - Cheng-Ta Tsai
- The Institute of Physical Education, Kokushikan University, Tokyo 206-8515, Japan
| | - Naoki Suzuki
- Department of Rehabilitation Medicine, Graduate School of Medicine, Tohoku University, Miyagi 980-8575, Japan
| | - Kazutaka Murayama
- Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Miyagi 980-8575, Japan
| | - Masaki Kaneko
- The Institute of Physical Education, Kokushikan University, Tokyo 206-8515, Japan
| | - Katsuhiko Hata
- Department of Sports and Medical Science, Graduate School of Emergency Medical System, Kokushikan University, Tokyo 206-8515, Japan
| | - Hiroaki Takada
- Designing Future Health Initiative, Center for Promotion of Innovation Strategy, Head Office of Enterprise Partnerships, Tohoku University, Miyagi 980-8579, Japan
| | - Yutaka Kano
- Center for Neuroscience and Biomedical Engineering, University of Electro-Communications, Tokyo 182-8585, Japan; Department of Engineering Science, Graduate School of Informatics and Engineering, University of Electro-Communications, Tokyo 182-8585, Japan
| | - Ryoichi Nagatomi
- Designing Future Health Initiative, Center for Promotion of Innovation Strategy, Head Office of Enterprise Partnerships, Tohoku University, Miyagi 980-8579, Japan.
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Mazzolini L, Touriol C. PERK-Olating Through Cancer: A Brew of Cellular Decisions. Biomolecules 2025; 15:248. [PMID: 40001551 PMCID: PMC11852789 DOI: 10.3390/biom15020248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/24/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane protein that plays a multifaceted role in cancer development and progression, influencing tumor growth, metastasis, and cellular stress responses. The activation of PERK represents one of the three signaling pathways induced during the unfolded protein response (UPR), which is triggered, in particular, in tumor cells that constitutively experience various intracellular and extracellular stresses that impair protein folding within the ER. PERK activation can lead to both pro-survival and proapoptotic outcomes, depending on the cellular context and the extent of ER stress. It helps the reprogramming of the gene expression in cancer cells, thereby ensuring survival in the face of oncogenic stress, such as replicative stress and DNA damage, and also microenvironmental challenges, including hypoxia, angiogenesis, and metastasis. Consequently, PERK contributes to tumor initiation, transformation, adaptation to the microenvironment, and chemoresistance. However, sustained PERK activation in cells can also impair cell proliferation and promote apoptotic death by various interconnected processes, including mitochondrial dysfunction, translational inhibition, the accumulation of various cellular stresses, and the specific induction of multifunctional proapoptotic factors, such as CHOP. The dual role of PERK in promoting both tumor progression and suppression makes it a complex target for therapeutic interventions. A comprehensive understanding of the intricacies of PERK pathway activation and their impact is essential for the development of effective therapeutic strategies, particularly in diseases like cancer, where the ER stress response is deregulated in most, if not all, of the solid and liquid tumors. This article provides an overview of the knowledge acquired from the study of animal models of cancer and tumor cell lines cultured in vitro on PERK's intracellular functions and their impact on cancer cells and their microenvironment, thus highlighting potential new therapeutic avenues that could target this protein.
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Hu H, Wen F, Zhen T, Zhang M, Qin J, Huang J, Chen Z, Yu M, Hu S, Fang M, Zeng JZ. Design, synthesis, and biological evaluation of N 1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N 2-(substituent)-1,2-dicarboxamides as anticancer agents targeting Nur77-mediated endoplasmic reticulum stress. Bioorg Chem 2025; 155:108113. [PMID: 39787915 DOI: 10.1016/j.bioorg.2024.108113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/17/2024] [Accepted: 12/28/2024] [Indexed: 01/12/2025]
Abstract
Targeting endoplasmic reticulum (ER) stress-induced apoptosis has attracted considerable research interest in anti-cancer drug development. Nur77 is a potential therapeutic target in many cancers and several Nur77 modulators have recently been identified as effective anticancer agents by activating ER stress. As an ongoing work, this study reports a new series of novel N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as potent Nur77 modulators that cause ER stress-induced apoptosis. Among this new series, most compounds show improved cytotoxicity against liver cancer (HepG2 and Huh7) and breast cancer (MCF-7 and MDA-MB-231) cell lines. The representative analog 15h dramatically induces Nur77 expression and cell apoptosis, showing excellent growth inhibition of HepG2 and MCF-7 cells (IC50 < 5.0 μM). Mechanistically, 15h binds (KD = 0.477 μM) and activates Nur77-mediated ER stress through the PERK-ATF4 and IRE1 signaling pathways, thereby inducing cell apoptosis. In vivo, 15h treatment strongly suppresses HepG2 xenograft tumor growth (tumor shrink by 54.06 %). In summary, we synthesize a series of novel indole derivatives, among which 15h has significantly improved pharmacological activity against various cancer cells. We further identify 15h as a novel ligand of Nur77, which may serve a therapeutic lead for developing new cancer therapy.
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Affiliation(s)
- Hongyu Hu
- Xingzhi College, Zhejiang Normal University, Lanxi 321004, China
| | - Fangfang Wen
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China; Community Health Service Center of Dashi Panyu, Guangzhou 511430, China
| | - Tidong Zhen
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Minda Zhang
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Jingbo Qin
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Jiangang Huang
- Xingzhi College, Zhejiang Normal University, Lanxi 321004, China
| | - Zhirong Chen
- The Second People's Hospital of Panyu Guangzhou, Guangzhou 511430, China
| | - Mingyue Yu
- Xingzhi College, Zhejiang Normal University, Lanxi 321004, China; College of Chemsitry and Bioengineering, Yichun 336000, China
| | - Shengwei Hu
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China
| | - Meijuan Fang
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
| | - Jin-Zhang Zeng
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
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Shin GS, Park Y, Kim JY, Kim CH, An MJ, Lee HM, Jo AR, Kim J, Hwangbo Y, Kim JW. Propylparaben-induced endoplasmic reticulum stress triggers G2/M phase cell cycle arrest and initiates caspase-3-dependent apoptosis in human lung cells. Genes Genomics 2025; 47:223-233. [PMID: 39699851 DOI: 10.1007/s13258-024-01605-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/01/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND Propylparaben (PrP) is commonly used as an antimicrobial agent in food, cosmetics, and pharmaceuticals. While recent studies have shown that PrP exposure can cause various disruptions in cellular physiology, the precise mechanisms behind these effects remain unclear. OBJECTIVE In this study, we sought to examine the cytotoxic effects of PrP exposure on human lung cells in a dose- and time-dependent manner. We utilized flow cytometry to analyze the expression of proteins associated with the cell cycle and apoptosis at the single-cell level. RESULTS Our results showed that PrP treatment leads to a significant upregulation of genes related to ER stress. The activation of ER stress results in a decrease in cyclin B1 levels, which subsequently causes cell cycle arrest at the G2/M phase. After 48 h of PrP exposure, the unfolded protein response (UPR) triggers an apoptotic signaling pathway, increasing the number of cells undergoing caspase-3-mediated apoptosis. Together, these physiological changes lead to a reduction in cell viability in the presence of PrP. CONCLUSION These findings suggest that PrP exerts harmful effects on human lung cells by activating ER stress, which can lead to apoptosis and cell cycle arrest.
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Affiliation(s)
- Geun-Seup Shin
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Yuna Park
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Ji-Young Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Chul-Hong Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Mi-Jin An
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Hyun-Min Lee
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Ah-Ra Jo
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jinho Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Yujeong Hwangbo
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Kennedy BB, Raza M, Mirza S, Rajan AR, Oruji F, Storck MM, Lele SM, Reznicek TE, Li L, Rowley MJ, Wan S, Mohapatra BC, Band H, Band V. ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.28.635284. [PMID: 39975123 PMCID: PMC11838291 DOI: 10.1101/2025.01.28.635284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
The ecdysoneless (ECD) mRNA and protein are overexpressed in breast cancer (BC), and its overexpression correlates with poor prognosis and short patient survival, particularly in ERBB2/HER2-positive BC. This study investigates the co-operative oncogenic mechanism of ECD and ERBB2 by deriving transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under MMTV promoter, as well as human mammary immortal epithelial cell lines (hMECs) overexpressing ECD and/or ERBB2. While huHER2 Tg mice developed more homogenous solid nodular carcinomas, double transgenic mice ( ECD;huHER2 Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, like ECD Tg tumors, resembling more to patient tumors. Importantly, transcriptomic profile of ECD;huHER2 Tg tumors revealed upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis. Similarly, hMECs expressing both ECD and ERBB2 as compared to single gene expressing cells showed increase in oncogenic traits, and RNA-seq analysis showed a significant upregulation of glycolysis and UPR pathways. ECD is an RNA binding protein, and directly associates with three key glycolytic enzymes ( LDHA , PKM2 and HK2 ) and mRNA of a major UPR regulated gene GRP78, that results in increased mRNA stability. Lastly, we show an increase in glucose uptake and enhanced glycolytic rate in ECD+ERBB2-overexpressing cells as compared to ECD- or ERBB2-overexpressing hMECs. Taken together, our findings support a co-operative role of ECD and ERBB2 in oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis. Significance This study provides mechanistic insights that overexpression of ECD in ERBB2+ breast cancer patients correlates with shorter patient survival, by identifying direct ECD binding to mRNAs for UPR and glycolysis pathways.
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Zhang J, Liu J, Ni J, Lin X, Fan L, Sun G. Exosomes Derived from Endoplasmic Reticulum Stressed Hepatocellular Carcinoma Cells Enhance the Antitumor Immunity of Dendritic Cells. Inflammation 2024:10.1007/s10753-024-02214-z. [PMID: 39714721 DOI: 10.1007/s10753-024-02214-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 12/24/2024]
Abstract
Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism. We found that ER-stressed HCC cells secreted more exosomes (EXO-TM) than those without ER stress (EXO-CON) and that exosomes were effectively taken up by DCs. EXO-TM significantly promoted DCs maturation, as demonstrated by the increased expression of HLA-ABC, CD83, CD80, CD86, and pro-inflammatory cytokines and the decreased expression of IL-10. Moreover, EXO-TM pulsed DCs (DCEXO-TM) significantly enhanced T lymphocyte-mediated lysis against several types of tumor cells by promoting the proliferation of CD3+CD8+ T cells and increasing the expression of INF-γ both in vitro and in vivo. Mechanistically, we found that heat shock protein (HSP) 90 was more significantly enriched in EXO-TM than in EXO-CON cells, and the knockdown of HSP90 remarkably reversed EXO-TM-mediated DC activation. Our results suggest that exosomes derived from ER-stressed HCC cells could enhance the antitumor effect of DC-mediated T lymphocytes, which may be related to the large amount of HSP90 carried in the exosomes. Therefore, regulating the HSP90 carrying capacity of tumor exosomes may be an effective immunotherapy strategy.
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Affiliation(s)
- Ju Zhang
- Department of Clinical Laboratory, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jiatao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jing Ni
- Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiao Lin
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Lulu Fan
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
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Yoo D, Wu S, Choi S, Huh SO, Sadra A. STK33 as the functional substrate of miR-454-3p for suppression and apoptosis in neuroblastoma. Mol Cells 2024; 47:100145. [PMID: 39515612 PMCID: PMC11863495 DOI: 10.1016/j.mocell.2024.100145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
miR-454-3p has been reported to be a tumor-suppressive microRNA (miRNA) in multiple cancer types. We identified the kinase STK33 mRNA, which is a high-risk factor for survival in neuroblastoma (NB) patients, as being a substrate of miR-454-3p in NB. Even though STK33 is an attractive target for several cancers, the development of inhibitors of STK33 has been challenging. For the various cell lines tested, we demonstrated reduced growth and viability with the miR-454-3p mimic. From among the candidate NB-associated miRNAs, miR-454-3p mimic and its antagonist had the most profound effect on STK33 mRNA and protein-level changes. Under various conditions of growth and external stress for the cells, the RNA levels for miR-454-3p and STK33 also negatively correlated. Luciferase reporter assays demonstrated STK33 as a substrate for miR-454-3p, and recombinant versions of STK33 resistant to miR-454-3p significantly blunted the suppressive effect of the miR-454-3p and established STK33 as the major functional substrate of miR-454-3p. Overexpression of miR-454-3p or knockdown of STK33 mRNA promoted autophagy and at the same time, increased the apoptotic markers in the tested NB cells, indicating a mechanism for the suppressive effect of the agents. Given the difficult-to-drug targets such as STK33 and the recent successes in RNA delivery methods for cancer treatment, it is thought that targeting cancer cells with a suppressive miRNA such as miR-454-3p for STK33-dependent cancer types may be an alternative means of NB therapy.
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Affiliation(s)
- Dongkwan Yoo
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon, Gangwon State, Republic of Korea
| | - Sichen Wu
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon, Gangwon State, Republic of Korea
| | - Seunghyuk Choi
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon, Gangwon State, Republic of Korea
| | - Sung-Oh Huh
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon, Gangwon State, Republic of Korea.
| | - Ali Sadra
- Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chuncheon, Gangwon State, Republic of Korea.
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Sun Z, Wang J, Ji Z, Ma J, Chen Y, Jiao G. Ortho-silicic Acid Prevents Glucocorticoid-Induced Femoral Head Necrosis by Promoting Akt Phosphorylation to Inhibit Endoplasmic Reticulum Stress-Mediated Apoptosis and Enhance Angiogenesis and Osteogenesis. Biol Trace Elem Res 2024; 202:4988-4999. [PMID: 38177717 DOI: 10.1007/s12011-023-04048-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024]
Abstract
Glucocorticoid-induced osteonecrosis of the femoral head (SONFH) is the most prevalent form of secondary osteonecrosis affecting the femoral head. Glucocorticoids can cause damage to both vascular endothelial cells and osteoblasts. Previous studies have demonstrated that silicon can improve the resistance of vascular endothelial cells to oxidative stress and positively impact bone health. However, the impact of silicon on SONFH has yet to be investigated. We examined the influence of ortho-silicic acid (OSA, Si(OH)4) on the apoptosis and proliferation of vascular endothelial cells after glucocorticoid induction. Additionally, we evaluated the expression of apoptosis-related genes such as cleaved-caspase-3, Bcl-2 and Bax. The impact of glucocorticoids and OSA on the function of vascular endothelial cells was evaluated through wound healing, transwell and angiogenesis assays. Osteogenic function was subsequently evaluated through alizarin red staining, alkaline phosphatase staining and expression levels of osteogenic genes like RUNX2 and ALP. Moreover, we investigated the potential role of OSA in vivo using the SONFH animal model. At concentrations below 100 μM, OSA exhibits no toxicity on vascular endothelial cells and effectively reverses glucocorticoid-induced apoptosis in these cells. OSA increases the resilience of vascular endothelial cells against oxidative stress and enhances osteoblast differentiation. Our study revealed that glucocorticoids activate endoplasmic reticulum stress, a process that mediates the apoptosis of vascular endothelial cells. OSA ameliorated the endoplasmic reticulum stress associated with glucocorticoids through the increased expression of p-Akt levels. In vivo, OSA treatment effectively improved SONFH by enhancing vascular endothelial cell function and promoting osteogenic differentiation. OSA counteracted the adverse effects of glucocorticoids both in vitro and in vivo, demonstrating a beneficial therapeutic effect on SONFH.
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Affiliation(s)
- Zhenqian Sun
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China
- Shandong University, Wenhuaxi Road 107, Jinan, Shandong Province, People's Republic of China
| | - Jian Wang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China
- Shandong University, Wenhuaxi Road 107, Jinan, Shandong Province, People's Republic of China
| | - Zhongjie Ji
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China
- Shandong University, Wenhuaxi Road 107, Jinan, Shandong Province, People's Republic of China
| | - Jinlong Ma
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China
- Shandong University, Wenhuaxi Road 107, Jinan, Shandong Province, People's Republic of China
| | - Yunzhen Chen
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China.
| | - Guangjun Jiao
- Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People's Republic of China.
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Nair KA, Liu B. Navigating the landscape of the unfolded protein response in CD8 + T cells. Front Immunol 2024; 15:1427859. [PMID: 39026685 PMCID: PMC11254671 DOI: 10.3389/fimmu.2024.1427859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024] Open
Abstract
Endoplasmic reticulum stress occurs due to large amounts of misfolded proteins, hypoxia, nutrient deprivation, and more. The unfolded protein is a complex intracellular signaling network designed to operate under this stress. Composed of three individual arms, inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor-6, the unfolded protein response looks to resolve stress and return to proteostasis. The CD8+ T cell is a critical cell type for the adaptive immune system. The unfolded protein response has been shown to have a wide-ranging spectrum of effects on CD8+ T cells. CD8+ T cells undergo cellular stress during activation and due to environmental insults. However, the magnitude of the effects this response has on CD8+ T cells is still understudied. Thus, studying these pathways is important to unraveling the inner machinations of these powerful cells. In this review, we will highlight the recent literature in this field, summarize the three pathways of the unfolded protein response, and discuss their roles in CD8+ T cell biology and functionality.
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Affiliation(s)
- Keith Alan Nair
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
- The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Bei Liu
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
- The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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11
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Chowdhury SP, Solley SC, Polishchuk E, Bacal J, Conrad JE, Gardner BM, Acosta-Alvear D, Zappa F. Baseline unfolded protein response signaling adjusts the timing of the mammalian cell cycle. Mol Biol Cell 2024; 35:br12. [PMID: 38656789 PMCID: PMC11238080 DOI: 10.1091/mbc.e23-11-0419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 04/16/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024] Open
Abstract
The endoplasmic reticulum (ER) is a single-copy organelle that cannot be generated de novo, suggesting coordination between the mechanisms overseeing ER integrity and those controlling the cell cycle to maintain organelle inheritance. The Unfolded Protein Response (UPR) is a conserved signaling network that regulates ER homeostasis. Here, we show that pharmacological and genetic inhibition of the UPR sensors IRE1, ATF6, and PERK in unstressed cells delays the cell cycle, with PERK inhibition showing the most penetrant effect, which was associated with a slowdown of the G1-to-S/G2 transition. Treatment with the small molecule ISRIB to bypass the effects of PERK-dependent phosphorylation of the translation initiation factor eIF2α had no such effect, suggesting that cell cycle timing depends on PERK's kinase activity but is independent of eIF2α phosphorylation. Using complementary light and electron microscopy and flow cytometry-based analyses, we also demonstrate that the ER enlarges before mitosis. Together, our results suggest coordination between UPR signaling and the cell cycle to maintain ER physiology during cell division.
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Affiliation(s)
- Soham P. Chowdhury
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
| | - Sabrina C. Solley
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
| | - Elena Polishchuk
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Naples, Italy
| | - Julien Bacal
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
| | - Julia E. Conrad
- Altos Labs Bay Area Institute of Science, Altos Labs, Redwood City, CA 94065
| | - Brooke M. Gardner
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
| | - Diego Acosta-Alvear
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
| | - Francesca Zappa
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106
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12
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Song J, Ham J, Song G, Lim W. Osthole Suppresses Cell Growth of Prostate Cancer by Disrupting Redox Homeostasis, Mitochondrial Function, and Regulation of tiRNA HisGTG. Antioxidants (Basel) 2024; 13:669. [PMID: 38929108 PMCID: PMC11201130 DOI: 10.3390/antiox13060669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/16/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Prostate cancer remains a significant global health concern, posing a substantial threat to men's well-being. Despite advancements in treatment modalities, the progression of prostate cancer still presents challenges, warranting further exploration of novel therapeutic strategies. In this study, osthole, a natural coumarin derivative, inhibited cell viability in cancer cells but not in the normal prostate cell line. Moreover, osthole disrupted cell cycle progression. Furthermore, osthole reduces mitochondrial respiration with mitochondrial membrane potential (ΔΨm) depolarization and reactive oxygen species (ROS) generation, indicating mitochondrial dysfunction. In particular, osthole-induced ROS generation was reduced by N-acetyl-L-cysteine (NAC) in prostate cancer. In addition, using calcium inhibitors (2-APB and ruthenium red) and endoplasmic reticulum (ER) stress inhibitor (4-PBA), we confirmed that ER stress-induced calcium overload by osthole causes mitochondrial dysfunction. Moreover, we verified that the osthole-induced upregulation of tiRNAHisGTG expression is related to mechanisms that induce permeabilization of the mitochondrial membrane and calcium accumulation. Regarding intracellular signaling, osthole inactivated the PI3K and ERK pathways while activating the expression of the P38, JNK, ER stress, and autophagy-related proteins. In conclusion, the results suggest that osthole can be used as a therapeutic or adjuvant treatment for the management of prostate cancer.
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Affiliation(s)
- Jisoo Song
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea;
| | - Jiyeon Ham
- Division of Animal and Dairy Science, College of Agriculture and Life Sciences, Chungnam National University, Daejeon 34134, Republic of Korea;
| | - Gwonhwa Song
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea
| | - Whasun Lim
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea;
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13
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Shidoji Y. Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid-A Comparison with Palmitic Acid and Retinoic Acid. Cells 2024; 13:809. [PMID: 38786033 PMCID: PMC11119665 DOI: 10.3390/cells13100809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/05/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.
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Affiliation(s)
- Yoshihiro Shidoji
- Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan
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14
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González-Cota AL, Martínez-Flores D, Rosendo-Pineda MJ, Vaca L. NMDA receptor-mediated Ca 2+ signaling: Impact on cell cycle regulation and the development of neurodegenerative diseases and cancer. Cell Calcium 2024; 119:102856. [PMID: 38408411 DOI: 10.1016/j.ceca.2024.102856] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/08/2024] [Accepted: 02/07/2024] [Indexed: 02/28/2024]
Abstract
NMDA receptors are Ca2+-permeable ligand-gated ion channels that mediate fast excitatory transmission in the central nervous system. NMDA receptors regulate the proliferation and differentiation of neural progenitor cells and also play critical roles in neural plasticity, memory, and learning. In addition to their physiological role, NMDA receptors are also involved in glutamate-mediated excitotoxicity, which results from excessive glutamate stimulation, leading to Ca2+ overload, and ultimately to neuronal death. Thus, NMDA receptor-mediated excitotoxicity has been linked to several neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, dementia, and stroke. Interestingly, in addition to its effects on cell death, aberrant expression or activation of NMDA receptors is also involved in pathological cellular proliferation, and is implicated in the invasion and proliferation of various types of cancer. These disorders are thought to be related to the contribution of NMDA receptors to cell proliferation and cell death through cell cycle modulation. This review aims to discuss the evidence implicating NMDA receptor activity in cell cycle regulation and the link between aberrant NMDA receptor activity and the development of neurodegenerative diseases and cancer due to cell cycle dysregulation. The information presented here will provide insights into the signaling pathways and the contribution of NMDA receptors to these diseases, and suggests that NMDA receptors are promising targets for the prevention and treatment of these diseases, which are leading causes of death and disability worldwide.
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Affiliation(s)
- Ana L González-Cota
- Instituto de Fisiología Celular, Departamento de Biología Celular y Desarrollo, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico
| | - Daniel Martínez-Flores
- Instituto de Fisiología Celular, Departamento de Biología Celular y Desarrollo, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico
| | - Margarita Jacaranda Rosendo-Pineda
- Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico
| | - Luis Vaca
- Instituto de Fisiología Celular, Departamento de Biología Celular y Desarrollo, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico.
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15
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Yang FW, Mai TL, Lin YCJ, Chen YC, Kuo SC, Lin CM, Lee MH, Su JC. Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer. Arch Pharm (Weinheim) 2024; 357:e2300435. [PMID: 38314850 DOI: 10.1002/ardp.202300435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 11/26/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.
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Affiliation(s)
- Fan-Wei Yang
- Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Te-Lun Mai
- Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Ying-Chung Jimmy Lin
- Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
- Institute of Plant Biology, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Chen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Shang-Che Kuo
- Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
| | - Chia-Ming Lin
- Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Meng-Hsuan Lee
- Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jung-Chen Su
- Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
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16
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Aceves M, Granados J, Leandro AC, Peralta J, Glahn DC, Williams-Blangero S, Curran JE, Blangero J, Kumar S. Role of Neurocellular Endoplasmic Reticulum Stress Response in Alzheimer's Disease and Related Dementias Risk. Genes (Basel) 2024; 15:569. [PMID: 38790197 PMCID: PMC11121587 DOI: 10.3390/genes15050569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's Disease and Related Dementias (ADRD) accounts for nearly 60-70% of all those cases. The spread of Alzheimer's Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD's causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs' ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs' transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.
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Affiliation(s)
- Miriam Aceves
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (M.A.); (J.G.)
| | - Jose Granados
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (M.A.); (J.G.)
| | - Ana C. Leandro
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (A.C.L.); (J.P.); (S.W.-B.); (J.E.C.); (J.B.)
| | - Juan Peralta
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (A.C.L.); (J.P.); (S.W.-B.); (J.E.C.); (J.B.)
| | - David C. Glahn
- Department of Psychiatry, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Sarah Williams-Blangero
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (A.C.L.); (J.P.); (S.W.-B.); (J.E.C.); (J.B.)
| | - Joanne E. Curran
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (A.C.L.); (J.P.); (S.W.-B.); (J.E.C.); (J.B.)
| | - John Blangero
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA; (A.C.L.); (J.P.); (S.W.-B.); (J.E.C.); (J.B.)
| | - Satish Kumar
- Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, McAllen, TX 78504, USA; (M.A.); (J.G.)
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17
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Dey N, Koumenis C, Ruggero D, Fuchs SY, Diehl JA. miR-217 Regulates Normal and Tumor Cell Fate Following Induction of Endoplasmic Reticulum Stress. Mol Cancer Res 2024; 22:360-372. [PMID: 38236939 PMCID: PMC10987263 DOI: 10.1158/1541-7786.mcr-23-0676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 01/26/2024]
Abstract
Rapidly proliferating cancer cells require a microenvironment where essential metabolic nutrients like glucose, oxygen, and growth factors become scarce as the tumor volume surpasses the established vascular capacity of the tissue. Limits in nutrient availability typically trigger growth arrest and/or apoptosis to prevent cellular expansion. However, tumor cells frequently co-opt cellular survival pathways thereby favoring cell survival under this environmental stress. The unfolded protein response (UPR) pathway is typically engaged by tumor cells to favor adaptation to stress. PERK, an endoplasmic reticulum (ER) protein kinase and UPR effector is activated in tumor cells and contributes tumor cell adaptation by limiting protein translation and balancing redox stress. PERK also induces miRNAs that contribute to tumor adaptation. miR-211 and miR-216b were previously identified as PERK-ATF4-regulated miRNAs that regulate cell survival. We have identified another PERK-responsive miRNA, miR-217, with increased expression under prolonged ER stress. Key targets of miR-217 are identified as TRPM1, the host gene for miR-211 and EZH2. Evidence is provided that miR-217 expression is essential for the rapid loss of miR-211 in prolonged ER stress and provides a functional link for determining whether cells adapt to stress or commit to apoptosis. IMPLICATIONS PERK-dependent induction of miR-217 limits accumulation and function of the prosurvival miRNA, miR-211, to establish cell fate and promote cell commitment to apoptosis.
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Affiliation(s)
- Neekkan Dey
- Department of Biochemistry, Case Comprehensive Cancer Center; Case Western Reserve University, Cleveland, OH 44106, USA
| | - Costas Koumenis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Davide Ruggero
- Departments of Urology and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Serge Y. Fuchs
- Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - J. Alan Diehl
- Department of Biochemistry, Case Comprehensive Cancer Center; Case Western Reserve University, Cleveland, OH 44106, USA
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18
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Köberlin MS, Fan Y, Liu C, Chung M, Pinto AFM, Jackson PK, Saghatelian A, Meyer T. A fast-acting lipid checkpoint in G1 prevents mitotic defects. Nat Commun 2024; 15:2441. [PMID: 38499565 PMCID: PMC10948896 DOI: 10.1038/s41467-024-46696-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 03/06/2024] [Indexed: 03/20/2024] Open
Abstract
Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass, but how insufficient synthesis restricts cell-cycle entry is not understood. Here, we identify a lipid checkpoint in G1 phase of the mammalian cell cycle by using live single-cell imaging, lipidome, and transcriptome analysis of a non-transformed cell. We show that synthesis of fatty acids in G1 not only increases lipid mass but extensively shifts the lipid composition to unsaturated phospholipids and neutral lipids. Strikingly, acute lowering of lipid synthesis rapidly activates the PERK/ATF4 endoplasmic reticulum (ER) stress pathway that blocks cell-cycle entry by increasing p21 levels, decreasing Cyclin D levels, and suppressing Retinoblastoma protein phosphorylation. Together, our study identifies a rapid anticipatory ER lipid checkpoint in G1 that prevents cells from starting the cell cycle as long as lipid synthesis is low, thereby preventing mitotic defects, which are triggered by low lipid synthesis much later in mitosis.
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Affiliation(s)
- Marielle S Köberlin
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - Yilin Fan
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Chad Liu
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA, 94111, USA
| | - Mingyu Chung
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Antonio F M Pinto
- Clayton Foundation Laboratories for Peptide Biology and Mass Spectrometry Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Peter K Jackson
- Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Alan Saghatelian
- Clayton Foundation Laboratories for Peptide Biology and Mass Spectrometry Core, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Tobias Meyer
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, 10065, USA.
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19
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Karamali N, Daraei A, Rostamlou A, Mahdavi R, Akbari Jonoush Z, Ghadiri N, Mahmoudi Z, Mardi A, Javidan M, Sohrabi S, Baradaran B. Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer. Cancer Cell Int 2024; 24:104. [PMID: 38468244 PMCID: PMC10926595 DOI: 10.1186/s12935-024-03296-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 03/06/2024] [Indexed: 03/13/2024] Open
Abstract
Breast cancer is significantly influenced by endoplasmic reticulum (ER) stress, impacting both its initiation and progression. When cells experience an accumulation of misfolded or unfolded proteins, they activate the unfolded protein response (UPR) to restore cellular balance. In breast cancer, the UPR is frequently triggered due to challenging conditions within tumors. The UPR has a dual impact on breast cancer. On one hand, it can contribute to tumor growth by enhancing cell survival and resistance to programmed cell death in unfavorable environments. On the other hand, prolonged and severe ER stress can trigger cell death mechanisms, limiting tumor progression. Furthermore, ER stress has been linked to the regulation of non-coding RNAs (ncRNAs) in breast cancer cells. These ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in cancer development by influencing gene expression and cellular processes. An improved understanding of how ER stress and ncRNAs interact in breast cancer can potentially lead to new treatment approaches. Modifying specific ncRNAs involved in the ER stress response might interfere with cancer cell survival and induce cell death. Additionally, focusing on UPR-associated proteins that interact with ncRNAs could offer novel therapeutic possibilities. Therefore, this review provides a concise overview of the interconnection between ER stress and ncRNAs in breast cancer, elucidating the nuanced effects of the UPR on cell fate and emphasizing the regulatory roles of ncRNAs in breast cancer progression.
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Affiliation(s)
- Negin Karamali
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arshia Daraei
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arman Rostamlou
- Department of Medical Biology, School of Medicine, University of EGE, Bornova, Izmir, Turkey
| | - Roya Mahdavi
- Student Research Committee, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zahra Akbari Jonoush
- Student Research Committee, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nooshin Ghadiri
- Student Research Committee, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zahra Mahmoudi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amirhossein Mardi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Moslem Javidan
- Student Research Committee, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sepideh Sohrabi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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20
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Xu B, Jia Q, Liao X, Fan T, Mou L, Song Y, Zhu C, Yang T, Li Z, Wang M, Zhang Q, Liang L. Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diphthamide modification of eEF2. Cancer Lett 2024; 582:216591. [PMID: 38097134 DOI: 10.1016/j.canlet.2023.216591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 11/02/2023] [Accepted: 12/05/2023] [Indexed: 01/04/2024]
Abstract
Oxaliplatin is an important initial chemotherapy benefiting advanced-stage colorectal cancer patients. Frustratingly, acquired oxaliplatin resistance always occurs after sequential chemotherapy with diverse antineoplastic drugs. Therefore, an exploration of the mechanism of oxaliplatin resistance formation in-depth is urgently needed. We generated oxaliplatin-resistant colorectal cancer models by four representative compounds, and RNA-seq revealed that oxaliplatin resistance was mainly the result of cells' response to stimulus. Moreover, we proved persistent stimulus-induced endoplasmic reticulum stress (ERs) and associated cellular senescence were the core causes of oxaliplatin resistance. In addition, we screened diverse phytochemicals for ER inhibitors in silico, identifying inositol hexaphosphate (IP6), whose strong binding was confirmed by surface plasmon resonance. Finally, we confirmed the ability of IP6 to reverse colorectal cancer chemoresistance and investigated the mechanism of IP6 in the inhibition of diphthamide modification of eukaryotic elongation factor 2 (eEF2) and PERK activation. Our study demonstrated that oxaliplatin resistance contributed to cell senescence induced by persistently activated PERK and diphthamide modification of eEF2 levels, which were specifically reversed by combination therapy with IP6.
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Affiliation(s)
- Binghui Xu
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China
| | - Qingan Jia
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China
| | - Xia Liao
- Department of Nutrition, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an 710038, China
| | - Tian Fan
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Lei Mou
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Yuna Song
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Chunyu Zhu
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Tongling Yang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China
| | - Zhixian Li
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Miao Wang
- Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China
| | - Qiangbo Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China.
| | - Lei Liang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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21
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Kim LC, Lesner NP, Simon MC. Cancer Metabolism under Limiting Oxygen Conditions. Cold Spring Harb Perspect Med 2024; 14:a041542. [PMID: 37848248 PMCID: PMC10835619 DOI: 10.1101/cshperspect.a041542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2 Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.
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Affiliation(s)
- Laura C Kim
- Abramson Family Cancer Research Institute, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Nicholas P Lesner
- Abramson Family Cancer Research Institute, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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22
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Wan S, Li KP, Wang CY, Yang JW, Chen SY, Wang HB, Li XR, Yang L. Immunologic Crosstalk of Endoplasmic Reticulum Stress Signaling in Bladder Cancer. Curr Cancer Drug Targets 2024; 24:701-719. [PMID: 38265406 DOI: 10.2174/0115680096272663231121100515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/19/2023] [Accepted: 11/02/2023] [Indexed: 01/25/2024]
Abstract
Bladder cancer (BC) is a common malignant tumor of the urinary system. While current approaches involving adjuvant chemotherapy, radiotherapy, and immunotherapy have shown significant progress in BC treatment, challenges, such as recurrence and drug resistance, persist, especially in the case of muscle-invasive bladder cancer (MIBC). It is mainly due to the lack of pre-existing immune response cells in the tumor immune microenvironment. Micro-environmental changes (such as hypoxia and under-nutrition) can cause the aggregation of unfolded and misfolded proteins in the lumen, which induces endoplasmic reticulum (ER) stress. ER stress and its downstream signaling pathways are closely related to immunogenicity and tumor drug resistance. ER stress plays a pivotal role in a spectrum of processes within immune cells and the progression of BC cells, encompassing cell proliferation, autophagy, apoptosis, and resistance to therapies. Recent studies have increasingly recognized the potential of natural compounds to exhibit anti-BC properties through ER stress induction. Still, the efficacy of these natural compounds remains less than that of immune checkpoint inhibitors (ICIs). Currently, the ER stress-mediated immunogenic cell death (ICD) pathway is more encouraging, which can enhance ICI responses by mediating immune stemness. This article provides an overview of the recent developments in understanding how ER stress influences tumor immunity and its implications for BC. Targeting this pathway may soon emerge as a compelling therapeutic strategy for BC.
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Affiliation(s)
- Shun Wan
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
| | - Kun-Peng Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
| | - Chen-Yang Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou730000, PR China
| | - Jian-Wei Yang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
| | - Si-Yu Chen
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
| | - Hua-Bin Wang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
| | - Xiao-Ran Li
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
| | - Li Yang
- Department of Urology, Lanzhou University Second Hospital, Lanzhou, 730000, PR China
- Gansu Province Clinical Research Center for Urology, Lanzhou, 730000, PR China
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23
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Karamali N, Mahmoudi Z, Roghani SA, Assar S, Pournazari M, Soufivand P, Karaji AG, Rezaiemanesh A. Overexpression of Synoviolin and miR-125a-5p, miR-19b-3p in peripheral blood of rheumatoid arthritis patients after treatment with conventional DMARDs and methylprednisolone. Clin Rheumatol 2024; 43:147-157. [PMID: 38049563 DOI: 10.1007/s10067-023-06808-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 10/02/2023] [Accepted: 10/31/2023] [Indexed: 12/06/2023]
Abstract
PURPOSE SYVN1 is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase that has an essential function along with SEL1L in rheumatoid arthritis (RA) pathogenesis. This study aimed to investigate the changes in the expression of peripheral blood ncRNAs and SYVN1-SEL1L affected by DMARDs treatment. METHODS Twenty-five newly diagnosed RA patients were randomly assigned to receive conventional DMARDs (csDMARDs) and methylprednisolone for six months. The peripheral blood gene expression of SYVN1 and SEL1L and possible regulatory axes, NEAT1, miR-125a-5p, and miR-19b-3p, were evaluated before and after qRT-PCR. We also compared differences between the patients and healthy controls (HCs), and statistical analyses were performed to determine the correlation between ncRNAs with SYVN1-SEL1L and the clinical parameters of RA. RESULTS Expression of NEAT1 (P = 0.0001), miR-19b-3p (P = 0.007), miR-125a-5p (P = 0.005), and SYVN1 (P = 0.036) was significantly increased in newly diagnosed patients compared to HCs; also, miR-125a-5p, miR-19b-3p, and SYVN1 were significantly overexpressed after treatment (P = 0.001, P = 0.001, and P = 0.005, respectively). NEAT1 was positively correlated with SYVN1, and miR-125a-5p had a negative correlation with anti-cyclic citrullinated peptides. The ROC curve analysis showed the potential role of selected ncRNAs in RA pathogenesis. CONCLUSION The results indicate the ineffectiveness of the csDMARDs in reducing SYVN1 expression. The difference in expression of ncRNAs might be useful markers for monitoring disease activity and determining therapeutic responses in RA patients. Key Points • The expression of NEAT1 is significantly upregulated in RA patients compared to HC subjects. • miR-19b-3p, miR-125a-5p, and SYVN1 are significantly upregulated in RA patients compared to HC subjects. • The expression of miR-19b-3p and miR-125a-5p is significantly increased in RA patients after treatment with DMARDs and methylprednisolone. • NEAT1 is positively correlated with SYVN1.
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Affiliation(s)
- Negin Karamali
- Student Research Committee, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Mahmoudi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Askar Roghani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shirin Assar
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parviz Soufivand
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Gorgin Karaji
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, Kermanshah, 6714869914, Iran
| | - Alireza Rezaiemanesh
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Daneshgah Street, Shahid Shiroudi Boulevard, Kermanshah, 6714869914, Iran.
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24
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Liu K, Zhao C, Adajar RC, DeZwaan-McCabe D, Rutkowski DT. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. EMBO Rep 2024; 25:228-253. [PMID: 38177915 PMCID: PMC10897205 DOI: 10.1038/s44319-023-00026-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 01/06/2024] Open
Abstract
Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we combine a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we find that CHOP promotes death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP confers to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggest that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stresses of physiological intensity.
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Affiliation(s)
- Kaihua Liu
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Chaoxian Zhao
- Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Reed C Adajar
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Diane DeZwaan-McCabe
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - D Thomas Rutkowski
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
- Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
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25
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Liu K, Zhao C, Adajar RC, DeZwaan-McCabe D, Rutkowski DT. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.19.533325. [PMID: 36993175 PMCID: PMC10055232 DOI: 10.1101/2023.03.19.533325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we have combined a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we found that CHOP promoted death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP conferred to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggested that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stresses of physiological intensity.
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Affiliation(s)
- Kaihua Liu
- Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Chaoxian Zhao
- Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Reed C. Adajar
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Diane DeZwaan-McCabe
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
| | - D. Thomas Rutkowski
- Program in Human Toxicology, University of Iowa Carver College of Medicine, Iowa City, IA
- Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA
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26
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Lu X, Zhong L, Lindell E, Veanes M, Guo J, Zhao M, Salehi M, Swartling FJ, Chen X, Sjöblom T, Zhang X. Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells. Cell Death Dis 2023; 14:676. [PMID: 37833290 PMCID: PMC10576032 DOI: 10.1038/s41419-023-06204-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/20/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
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Affiliation(s)
- Xi Lu
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Lei Zhong
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, Sichuan, China
| | - Emma Lindell
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Margus Veanes
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Jing Guo
- Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore
| | - Miao Zhao
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Maede Salehi
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Fredrik J Swartling
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Xingqi Chen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Tobias Sjöblom
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Xiaonan Zhang
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
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27
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Luna-Marco C, Ubink A, Kopsida M, Heindryckx F. Endoplasmic Reticulum Stress and Metabolism in Hepatocellular Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1377-1388. [PMID: 36309104 DOI: 10.1016/j.ajpath.2022.09.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/23/2022] [Accepted: 09/20/2022] [Indexed: 11/05/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for 85% to 90% of all liver cancer cases. It is a hepatocyte-derived primary tumor, causing 550,000 deaths per year, ranking it as one of the most common cancers worldwide. The liver is a highly metabolic organ with multiple functions, including digestion, detoxification, breakdown of fats, and production of bile and cholesterol, in addition to storage of vitamins, glycogen, and minerals, and synthesizing plasma proteins and clotting factors. Due to these fundamental and diverse functions, the malignant transformation of hepatic cells can have a severe impact on the liver's metabolism. Furthermore, tumorigenesis is often accompanied by activation of the endoplasmic reticulum (ER) stress pathways, which are known to be highly intertwined with several metabolic pathways. Because HCC is characterized by changes in the metabolome and by an aberrant activation of the ER stress pathways, the aim of this review was to summarize the current knowledge that links ER stress and metabolism in HCC, thereby focusing on potential therapeutic targets.
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Affiliation(s)
- Clara Luna-Marco
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Anna Ubink
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Maria Kopsida
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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28
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Stump AL, Rioux DJ, Albright R, Melki GL, Prosser DC. Yeast Models of Amyotrophic Lateral Sclerosis Type 8 Mimic Phenotypes Seen in Mammalian Cells Expressing Mutant VAPB P56S. Biomolecules 2023; 13:1147. [PMID: 37509182 PMCID: PMC10377116 DOI: 10.3390/biom13071147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that results in the loss of motor neurons and can occur sporadically or due to genetic mutations. Among the 30 genes linked to familial ALS, a P56S mutation in VAPB, an ER-resident protein that functions at membrane contact sites, causes ALS type 8. Mammalian cells expressing VAPBP56S have distinctive phenotypes, including ER collapse, protein and/or membrane-containing inclusions, and sensitivity to ER stress. VAPB is conserved through evolution and has two homologs in budding yeast, SCS2 and SCS22. Previously, a humanized version of SCS2 bearing disease-linked mutations was described, and it caused Scs2-containing inclusions when overexpressed in yeast. Here, we describe a yeast model for ALS8 in which the two SCS genes are deleted and replaced with a single chromosomal copy of either wild-type or mutant yeast SCS2 or human VAPB expressed from the SCS2 promoter. These cells display ER collapse, the formation of inclusion-like structures, and sensitivity to tunicamycin, an ER stress-inducing drug. Based on the phenotypic similarity to mammalian cells expressing VAPBP56S, we propose that these models can be used to study the molecular basis of cell death or dysfunction in ALS8. Moreover, other conserved ALS-linked genes may create opportunities for the generation of yeast models of disease.
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Affiliation(s)
- AnnaMari L. Stump
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
- VCU Life Sciences, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Daniel J. Rioux
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
- VCU Life Sciences, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Richard Albright
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Guiliano L. Melki
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Derek C. Prosser
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
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29
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Liang W, Fu L, Feng M, Wang X, Yun Z, Xu J. Endoplasmic Reticulum Stress and Autophagy Are Involved in Hepatotoxicity Induced by Tributyltin. TOXICS 2023; 11:607. [PMID: 37505572 PMCID: PMC10386594 DOI: 10.3390/toxics11070607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/29/2023]
Abstract
Tributyltin (TBT), a common contaminant in aquatic ecosystems, has severe toxic effects on multiple tissues and organs, especially the liver. Previous toxicogenomic analysis has indicated that the main mechanism of TBT-induced hepatotoxicity is related to the activation of the apoptotic pathway. However, the mechanism of action occurring before the activation of apoptosis is still unclear. Herein, we applied proteomic technology to explore the protein expression profile of TBT-treated HL7702 normal human liver cells. The ultrastructural changes in cells were observed by transmission electron microscopy. After low dose (2 μΜ) TBT treatment, activation of the unfolded protein response and endoplasmic reticulum stress were observed; the expression levels of PERK, ATF6, BiP, and CHOP were significantly elevated, and splicing of XBP1 mRNA was initiated. When the TBT concentration increased to 4 μΜ, the protein levels of Beclin1, Atg3, Atg5, Atg7, and Atg12-Atg5 were significantly elevated, and the protein level of LC3Ⅰ decreased while that of LC3Ⅱ increased, suggesting the activation of autophagy. As the TBT concentration continued to increase, autophagy could not eliminate the damage, and apoptosis eventually occurred. These results indicate novel pathways of hepatotoxicity induced by TBT and provide insights for future studies.
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Affiliation(s)
- Weiqi Liang
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| | - Lingling Fu
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| | - Mei Feng
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| | - Xiaorong Wang
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| | - Zhaohui Yun
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| | - Jin Xu
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
- Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo 315211, China
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30
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Jiang W, Yang Z, Chen P, Zhao M, Wang Y, Wang J, Li X, Wang M, Hou P. Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1. Expert Opin Ther Targets 2023; 27:879-895. [PMID: 37704953 DOI: 10.1080/14728222.2023.2259097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 09/11/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy. RESEARCH DESIGN AND METHODS The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy. RESULTS Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype. CONCLUSIONS Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.
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Affiliation(s)
- Wei Jiang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Zhiwei Yang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi'an Jiaotong University, Xi'an, P.R. China
| | - Pu Chen
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Man Zhao
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yubo Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jingyuan Wang
- Department of Clinical Lab Diagnosis, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Xinru Li
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Meichen Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Peng Hou
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
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Shidoji Y. Geranylgeranoic acid, a bioactive and endogenous fatty acid in mammals: a review. J Lipid Res 2023:100396. [PMID: 37247782 PMCID: PMC10320608 DOI: 10.1016/j.jlr.2023.100396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 05/10/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023] Open
Abstract
Geranylgeranoic acid (GGA) was first reported in 1983 as one of the mevalonic acid (MVA) metabolites, but its biological significance was not studied for a long time. Our research on the antitumor effects of retinoids led us to GGA, one of the acyclic retinoids that induce cell death in human hepatoma-derived cell lines. We were able to demonstrate the presence of endogenous GGA in various tissues of male rats, including the liver, testis, and cerebrum, by LC-MS/MS. Furthermore, the biosynthesis of GGA from MVA in mammals including humans was confirmed by isotopomer spectral analysis using 13C-labeled mevalonolactone and cultured hepatoma cells, and the involvement of hepatic monoamine oxidase B (MAOB) in the biosynthesis of GGA was also demonstrated. The biological activity of GGA was analyzed from the retinoid (differentiation induction) and non-retinoid (cell death induction) aspects, and in particular, the non-retinoid mechanism by which GGA induces cell death in hepatoma cells was found to involve pyroptosis via ER-stress responses initiated by TLR4 signaling. In addition to these effects of GGA, we also describe the in vivo effects of GGA on reproduction. In this review, based mainly on our published papers, we have shown that hepatic MAOB is involved in the biosynthesis of GGA and that GGA induces cell death in human hepatoma-derived cell lines by non-canonical pyroptosis, one of the mechanisms of sterile inflammatory cell death.
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Affiliation(s)
- Yoshihiro Shidoji
- Molecular and Cellular Biology, University of Nagasaki, Nagayo, Nagasaki, Japan.
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32
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Amaresan R, Gopal U. Cell surface GRP78: a potential mechanism of therapeutic resistant tumors. Cancer Cell Int 2023; 23:100. [PMID: 37221596 DOI: 10.1186/s12935-023-02931-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/19/2023] [Indexed: 05/25/2023] Open
Abstract
GRP78 is a protein that acts as a chaperone within the endoplasmic reticulum (ER) and has multiple functions. It is induced by stress and abets cells from survival. Despite, multiple Stress conditions like ER, chronic psychological and nutritional stress, hypoxia, chemotherapy, radiation therapy, and drug resistance induce cell surface GRP78 (CS-GRP78) expression in cancer cells. Further, CS-GRP78 is associated with increased malignancy and resistance to anti-cancer therapies and is considered a high-value druggable target. Recent preclinical research suggests that targeting CS-GRP78 with anti-GRP78 monoclonal antibodies (Mab) in combination with other agents may be effective in reversing the failure of chemotherapy, radiotherapy, or targeted therapies and increasing the efficacy of solid tumors treatment. This article will review recent evidence on the role of CS-GRP78 in developing resistance to anti-cancer treatments and the potential benefits of combining anti-GRP78 Mab with other cancer therapies for specific patient populations. Furthermore, our limited understanding of how CS-GRP78 regulated in human studies is a major drawback for designing effective CS-GRP78-targeted therapies. Hence, more research is still warranted to translate these potential therapies into clinical applications.
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Affiliation(s)
- Rajalakshmi Amaresan
- Department of Zoology, Auxilium College, Gandhi Nagar, Vellore, 632 006, Tamil Nadu, India
| | - Udhayakumar Gopal
- Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
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Tan HY, Wan C, Wu GL, Qiao LJ, Cai YF, Wang Q, Zhang SJ. Taohong siwu decoction ameliorates cognitive dysfunction through SIRT6/ER stress pathway in Alzheimer's disease. JOURNAL OF ETHNOPHARMACOLOGY 2023; 314:116580. [PMID: 37142144 DOI: 10.1016/j.jep.2023.116580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 04/29/2023] [Accepted: 05/01/2023] [Indexed: 05/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE A growing number of people suffer from Alzheimer's disease (AD), but there is currently no effective treatment yet. Taohong Siwu Decoction (TSD) has been proved to take strong neuropharmacological activity on dementia, but the effect and mechanism of TSD against AD are still elusive. AIM OF STUDY To investigate whether TSD could be effective in ameliorating cognitive deficits through SIRT6/ER stress pathway. MATERIALS AND METHODS Herein, the APP/PS1 mice, an AD model, and HT-22 cell lines were utilized. Different dosages of TSD (4.25, 8.50 and 17.00 g/kg/d) were administered to the mice for 10 weeks by gavage. Following the behavioral tests, oxidative stress levels were measured using malondialdehyde (MDA) and superoxide dismutase (SOD) kits. Nissl staining and Western blot analyses were used to detect the neuronal function. Then, immunofluorescence and Western blot analysis were applied to evaluate silent information regulator 6 (SIRT6) and ER Stress related protein levels in APP/PS1 mice and HT-22 cells. RESULTS Behavioral tests revealed that APP/PS1 mice administered with TSD orally took more time in the target quadrant, crossed more times in the target quadrant, had a higher recognition coefficient, and spent more time in the central region. In addition, TSD could ameliorate oxidative stress and inhibit neuronal apoptosis in APP/PS1 mice. Furthermore, TSD could up-regulate the SIRT6 protein expression and inhibit ER sensing proteins expressions, such as p-PERK and ATF6, in APP/PS1 mice and Aβ1-42-treated HT22 cells. CONCLUSION According to the abovementioned findings, TSD could alleviate cognitive dysfunction in AD by modulating the SIRT6/ER stress pathway.
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Affiliation(s)
- Hong-Yu Tan
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Can Wan
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Guang-Liang Wu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Li-Jun Qiao
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Ye-Feng Cai
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Postdoctoral Research Station of Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Shi-Jie Zhang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Postdoctoral Research Station of Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
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Yu JE, Yeo IJ, Yoo SS, Kim SH, Son DJ, Yun J, Han SB, Hong JT. Induction of ER stress-mediated apoptosis through SOD1 upregulation by deficiency of CHI3L1 inhibits lung metastasis. Theranostics 2023; 13:2693-2709. [PMID: 37215572 PMCID: PMC10196820 DOI: 10.7150/thno.82898] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/21/2023] [Indexed: 05/24/2023] Open
Abstract
Chitinase-3-like protein 1 (CHI3L1), which is secreted by immune and inflammatory cells, is associated with several inflammatory diseases. However, the basic cellular pathophysiological functions of CHI3L1 are not well characterized. To investigate the novel pathophysiological function of CHI3L1, we performed LC-MS/MS analysis of cells transfected with Myc-vector and Myc-CHI3L1. We analyzed the changes in the protein distribution in Myc-CHI3L1 transfected-cells, and identified 451 differentially expressed proteins (DEPs) compared with Myc-vector-transfected-cells. The biological function of the 451 DEPs was analyzed and it was found that the proteins with endoplasmic reticulum (ER)-associated function were much more highly expressed in CHI3L1-overexpressing cells. We then compared and analyzed the effect of CHI3L1 on the ER chaperon levels in normal lung cells and cancer cells. We identified that CHI3L1 is localized in the ER. In normal cells, the depletion of CHI3L1 did not induce ER stress. However, the depletion of CHI3L1 induces ER stress and eventually activates the unfolded protein response, especially the activation of Protein kinase R-like endoplasmic reticulum kinase (PERK), which regulates protein synthesis in cancer cells. CHI3L1 may not affect ER stress owing to the lack of misfolded proteins in normal cells, but instead activate ER stress as a defense mechanism only in cancer cells. Under ER stress conditions induced by the application of thapsigargin, the depletion of CHI3L1 induces ER stress through the upregulation of PERK and PERK downstream factors (eIF2α and ATF4) in both normal and cancer cells. However, these signaling activations occur more often in cancer cells than in normal cells. The expression of Grp78 and PERK in the tissues of patients with lung cancer was higher compared with healthy tissues. It is well known that ER stress-mediated PERK-eIF2α-ATF4 signaling activation causes apoptotic cell death. ER stress-mediated apoptosis induced by the depletion of CHI3L1 occurs in cancer cells, but rarely occurs in normal cells. Consistent with results from the in vitro model, ER stress-mediated apoptosis was greatly increased during tumor growth and in the lung metastatic tissue of CHI3L1-knockout (KO) mice. The analysis of "big data" identified superoxide dismutase-1 (SOD1) as a novel target of CHI3L1 and interacted with CHI3L1. The depletion of CHI3L1 increased SOD1 expression, resulting in ER stress. Furthermore, the depletion of SOD1 reduced the expression of ER chaperones and ER-mediated apoptotic marker proteins, as well as apoptotic cell death induced by the depletion of CHI3L1 in in vivo and in vitro models. These results suggest that the depletion of CHI3L1 increases ER stress-mediated apoptotic cell death through SOD1 expression, and subsequently inhibits lung metastasis.
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Affiliation(s)
| | | | | | | | | | | | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
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Pu S, Pan Y, Zhang Q, You T, Yue T, Zhang Y, Wang M. Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury. Molecules 2023; 28:molecules28073160. [PMID: 37049925 PMCID: PMC10095764 DOI: 10.3390/molecules28073160] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/26/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Drug-induced liver injury (DILI) is a widespread and harmful disease closely linked to mitochondrial and endoplasmic reticulum stress (ERS). Globally, severe drug-induced hepatitis, cirrhosis, and liver cancer are the primary causes of liver-related morbidity and mortality. A hallmark of DILI is ERS and changes in mitochondrial morphology and function, which increase the production of reactive oxygen species (ROS) in a vicious cycle of mutually reinforcing stress responses. Several pathways are maladapted to maintain homeostasis during DILI. Here, we discuss the processes of liver injury caused by several types of drugs that induce hepatocyte stress, focusing primarily on DILI by ERS and mitochondrial stress. Importantly, both ERS and mitochondrial stress are mediated by the overproduction of ROS, destruction of Ca2+ homeostasis, and unfolded protein response (UPR). Additionally, we review new pathways and potential pharmacological targets for DILI to highlight new possibilities for DILI treatment and mitigation.
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Affiliation(s)
- Sisi Pu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yangyang Pan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Qian Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Ting You
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Tao Yue
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yuxing Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Meng Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
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36
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Lin DW, Hsu YC, Chang CC, Hsieh CC, Lin CL. Insights into the Molecular Mechanisms of NRF2 in Kidney Injury and Diseases. Int J Mol Sci 2023; 24:6053. [PMID: 37047024 PMCID: PMC10094034 DOI: 10.3390/ijms24076053] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 04/14/2023] Open
Abstract
Redox is a constant phenomenon in organisms. From the signaling pathway transduction to the oxidative stress during the inflammation and disease process, all are related to reduction-oxidation (redox). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor targeting many antioxidant genes. In non-stressed conditions, NRF2 maintains the hemostasis of redox with housekeeping work. It expresses constitutively with basal activity, maintained by Kelch-like-ECH-associated protein 1 (KEAP1)-associated ubiquitination and degradation. When encountering stress, it can be up-regulated by several mechanisms to exert its anti-oxidative ability in diseases or inflammatory processes to protect tissues and organs from further damage. From acute kidney injury to chronic kidney diseases, such as diabetic nephropathy or glomerular disease, many results of studies have suggested that, as a master of regulating redox, NRF2 is a therapeutic option. It was not until the early termination of the clinical phase 3 trial of diabetic nephropathy due to heart failure as an unexpected side effect that we renewed our understanding of NRF2. NRF2 is not just a simple antioxidant capacity but has pleiotropic activities, harmful or helpful, depending on the conditions and backgrounds.
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Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin de Porres Hospital, Chiayi 600, Taiwan;
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
| | - Cheng-Chih Chang
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan; (C.-C.C.); (C.-C.H.)
| | - Ching-Chuan Hsieh
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan; (C.-C.C.); (C.-C.H.)
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 105, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
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37
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Yu S, Zhao H, Qin X, Li X, Guo J, Li W. Giardia duodenalis-induced G0/G1 intestinal epithelial cell cycle arrest and apoptosis involve activation of endoplasmic reticulum stress in vitro. Front Immunol 2023; 14:1127552. [PMID: 37006313 PMCID: PMC10050679 DOI: 10.3389/fimmu.2023.1127552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/02/2023] [Indexed: 03/17/2023] Open
Abstract
Giardia duodenalis is a zoonotic intestinal protozoan parasite that may cause host diarrhea and chronic gastroenteritis, resulting in great economic losses annually and representing a significant public health burden across the world. However, thus far, our knowledge on the pathogenesis of Giardia and the related host cell responses is still extensively limited. The aim of this study is to assess the role of endoplasmic reticulum (ER) stress in regulating G0/G1 cell cycle arrest and apoptosis during in vitro infection of intestinal epithelial cells (IECs) with Giardia. The results showed that the mRNA levels of ER chaperone proteins and ER-associated degradation genes were increased and the expression levels of the main unfolded protein response (UPR)-related proteins (GRP78, p-PERK, ATF4, CHOP, p-IRE1, XBP1s and ATF6) were increased upon Giardia exposure. In addition, cell cycle arrest was determined to be induced by UPR signaling pathways (IRE1, PERK and ATF6) through upregulation of p21 and p27 levels and promotion of E2F1-RB complex formation. Upregulation of p21 and p27 expression was shown to be related to Ufd1-Skp2 signaling. Therefore, the cell cycle arrest was induced by ER stress when infected with Giardia. Furthermore, the apoptosis of the host cell was also assessed after exposure to Giardia. The results indicated that apoptosis would be promoted by UPR signaling (PERK and ATF6), but would be suppressed by the hyperphosphorylation of AKT and hypophosphorylation of JNK that were modulated by IRE1 pathway. Taken together, both of the cell cycle arrest and apoptosis of IECs induced by Giardia exposure involved the activation of the UPR signaling. The findings of this study will deepen our understanding of the pathogenesis of Giardia and the associated regulatory network.
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Affiliation(s)
| | | | | | | | | | - Wei Li
- *Correspondence: Wei Li, ; Jiaying Guo,
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38
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Chen RB, Wang QY, Wang YY, Wang YD, Liu JH, Liao ZZ, Xiao XH. Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1094458. [PMID: 36936164 PMCID: PMC10020511 DOI: 10.3389/fendo.2023.1094458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.
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Affiliation(s)
- Rong-Bin Chen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qi-Yu Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Pan J, Zhao R, Dong C, Yang J, Zhang R, Sun M, Ahmad N, Zhou Y, Liu Y. Cudraflavone B induces human glioblastoma cells apoptosis via ER stress-induced autophagy. BMC Neurosci 2023; 24:10. [PMID: 36721107 PMCID: PMC9890863 DOI: 10.1186/s12868-023-00778-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 01/24/2023] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common malignant intracranial tumor with a low survival rate. However, only few drugs responsible for GBM therpies, hence new drug development for it is highly required. The natural product Cudraflavone B (CUB) has been reported to potentially kill a variety of tumor cells. Currently, its anit-cancer effect on GBM still remains unknown. Herein, we investigated whether CUB could affect the proliferation and apoptosis of GBM cells to show anti-GBM potential. RESULTS CUB selectively inhibited cell viability and induced cell apoptosis by activating the endoplasmic reticulum stress (ER stress) related pathway, as well as harnessing the autophagy-related PI3K/mTOR/LC3B signaling pathway. Typical morphological changes of autophagy were also observed in CUB treated cells by microscope and scanning electron microscope (SEM) examination. 4-Phenylbutyric acid (4-PBA), an ER stress inhibitor, restored the CUB-caused alteration in signaling pathway and morphological change. CONCLUSIONS Our finding suggests that CUB impaired cell growth and induced cell apoptosis of glioblastoma through ER stress and autophagy-related signaling pathways, and it might be an attractive drug for treatment of GBM.
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Affiliation(s)
- Jinlin Pan
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China
| | - Rongchuan Zhao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China
| | - Caihua Dong
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China
| | - Jiao Yang
- Institute of Clinical Medicine Research, Suzhou Science & Technology Town Hospital, Suzhou, 215153, China
| | - Ruobing Zhang
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China
| | - Minxuan Sun
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China
| | - Nafees Ahmad
- Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan
| | - Yuanshuai Zhou
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
- Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Keling Road No.88, Suzhou, 215163, China.
| | - Yanxiang Liu
- Department of Pathology, Suzhou Science & Technology Town Hospital, No.1, Li Jiang Road, High-Tech District, Suzhou, 215153, China.
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Sec22b is a critical and nonredundant regulator of plasma cell maintenance. Proc Natl Acad Sci U S A 2023; 120:e2213056120. [PMID: 36595686 PMCID: PMC9926242 DOI: 10.1073/pnas.2213056120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, Sec22b-deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.
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Jiao B, Zhang M, Zhang C, Cao X, Liu B, Li N, Sun J, Zhang X. Transcriptomics reveals the effects of NTRK1 on endoplasmic reticulum stress response-associated genes in human neuronal cell lines. PeerJ 2023; 11:e15219. [PMID: 37070091 PMCID: PMC10105561 DOI: 10.7717/peerj.15219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/21/2023] [Indexed: 04/19/2023] Open
Abstract
Background NTRK1 gene, encoding TrkA, is essential for the nervous system and drives a variety of biological processes, including pain. Given the unsatisfied analgesic effects of some new drugs targeting NTRK1 in clinic, a deeper understanding for the mechanism of NTRK1 in neurons is crucial. Methods We assessed the transcriptional responses in SH-SY5Y cells with NTRK1 overexpression using bioinformatics analysis. GO and KEGG analyses were performed, PPI networks were constructed, and the functional modules and top 10 genes were screened. Subsequently, hub genes were validated using RT-qPCR. Results A total of 419 DEGs were identified, including 193 upregulated and 226 downregulated genes. GO showed that upregulated genes were mainly enriched in response to endoplasmic reticulum (ER) stress, protein folding in ER, etc., and downregulated genes were highly enriched in a series of cellular parts and cellular processes. KEGG showed DEGs were enriched in protein processing in ER and pathways associated with cell proliferation and migration. The finest module was dramatically enriched in the ER stress response-related biological process. The verified seven hub genes consisted of five upregulated genes (COL1A1, P4HB, HSPA5, THBS1, and XBP1) and two downregulated genes (CCND1 and COL3A1), and almost all were correlated with response to ER stress. Conclusion Our data demonstrated that NTRK1 significantly influenced the gene transcription of ER stress response in SH-SY5Y cells. It indicated that ER stress response could contribute to various functions of NTRK1-dependent neurons, and therefore, ER stress response-associated genes need further study for neurological dysfunction implicated in NTRK1.
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Affiliation(s)
- Bo Jiao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mi Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei Province, China
| | - Caixia Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xueqin Cao
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Baowen Liu
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ningbo Li
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jiaoli Sun
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xianwei Zhang
- Department of Anesthesiology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Qin L, Vetreno RP, Crews FT. NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder. Addict Biol 2023; 28:e13262. [PMID: 36577732 PMCID: PMC9811516 DOI: 10.1111/adb.13262] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/10/2022] [Accepted: 11/20/2022] [Indexed: 12/14/2022]
Abstract
Many disorders of the central nervous system (CNS), including alcohol use disorder (AUD), are associated with induction of proinflammatory neuroimmune signalling and neurodegeneration. In previous studies, we found increased expression of Toll-like receptors (TLRs), activated NF-κB p65 (RELA), and other proinflammatory signalling molecules. Proinflammatory NADPH oxidases generate reactive oxygen species, which are linked to neurodegeneration. We tested the hypothesis that AUD increased RELA activation increases NADPH oxidase-oxidative stress and endoplasmic reticulum (ER) stress cell death cascades in association with neuronal cell death in the human orbitofrontal cortex (OFC). In the AUD OFC, we report mRNA induction of several NADPH oxidases, the dual oxidase DUOX2, and the oxidative stress lipid peroxidation marker 4-HNE and the DNA oxidation marker 8-OHdG that correlate with RELA, a marker of proinflammatory NF-κB activation. This was accompanied by increased expression of the ER stress-associated regulator protein glucose-regulated protein 78 (GRP78), transmembrane sensors activating transcription factor 6 (ATF6), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and inositol-requiring kinase/endonuclease 1 (pIRE1), and the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Expression of NADPH oxidase-oxidative stress markers correlate with ER stress-associated molecules. Induction of oxidative stress and ER stress signalling pathways correlate with expression of cell death-associated caspases and neuronal cell loss. These data support the hypothesis that proinflammatory RELA-mediated induction of NADPH oxidase-oxidative stress and ER stress-associated signalling cascades is associated with neuronal cell death in the post-mortem human OFC of individuals with AUD.
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Affiliation(s)
- Liya Qin
- Bowles Center for Alcohol Studies, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Ryan P. Vetreno
- Bowles Center for Alcohol Studies, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Psychiatry, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Fulton T. Crews
- Bowles Center for Alcohol Studies, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Psychiatry, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Pharmacology, School of MedicineUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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Yu Y, Yang A, Yu G, Wang H. Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives. Biomolecules 2022; 12:1637. [PMID: 36358987 PMCID: PMC9687722 DOI: 10.3390/biom12111637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 09/08/2024] Open
Abstract
The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD.
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Affiliation(s)
| | | | - Ganggang Yu
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Haoyan Wang
- Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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44
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Wang T, Chen P, Weir S, Baltezor M, Schoenen FJ, Chen Q. Novel compound C150 inhibits pancreatic cancer through induction of ER stress and proteosome assembly. Front Oncol 2022; 12:870473. [PMID: 36276125 PMCID: PMC9579335 DOI: 10.3389/fonc.2022.870473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
Pancreatic cancer is a devastating disease with a dismal prognosis and poor treatment outcomes. Searching for new agents for pancreatic cancer treatment is of great significance. We previously identified a novel activity of compound C150 to inhibit pancreatic cancer epithelial-to-mesenchymal transition (EMT). Here, we further revealed its mechanism of action. C150 induced ER stress in pancreatic cancer cells and subsequently increased proteasome activity by enhancing proteasome assembly, which subsequently enhanced the degradation of critical EMT transcription factors (EMT-TFs). In addition, as cellular responses to ER stress, autophagy was elevated, and general protein synthesis was inhibited in pancreatic cancer cells. Besides EMT inhibition, the C150-induced ER stress resulted in G2/M cell cycle arrest, which halted cell proliferation and led to cellular senescence. In an orthotopic syngeneic mouse model, an oral dose of C150 at 150 mg/kg 3× weekly significantly increased survival of mice bearing pancreatic tumors, and reduced tumor growth and ascites occurrence. These results suggested that compound C150 holds promises in comprehensively inhibiting pancreatic cancer progression.
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Affiliation(s)
- Tao Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States
| | - Ping Chen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States
| | - Scott Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, United States
| | - Michael Baltezor
- Biotechnology Innovation and Optimization Center, University of Kansas, Lawrence, KS, United States
| | - Frank J. Schoenen
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
- Medicinal Chemistry Core Laboratory, Lead Development and Optimization Shared Resource, University of Kansas Cancer Center, Lawrence, KS, United States
| | - Qi Chen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States
- *Correspondence: Qi Chen,
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45
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Mogre S, Blazanin N, Walsh H, Ibinson J, Minnich C, Andrew Hu CC, Glick AB. TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes. Mol Carcinog 2022; 61:958-971. [PMID: 35975910 PMCID: PMC9486931 DOI: 10.1002/mc.23453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/25/2022] [Accepted: 06/08/2022] [Indexed: 11/08/2022]
Abstract
Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFβ1. Pharmacological and genetic approaches demonstrated that TGFβ1-dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK-dependent IRE1α phosphatase. In addition, TGFβ1-mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK-induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross-talk between UPR proteins that is important for TGFβ1-mediated tumor suppressive responses.
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Affiliation(s)
- Saie Mogre
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
| | - Nicholas Blazanin
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
| | - Hailey Walsh
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
| | - Jack Ibinson
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
| | - Chase Minnich
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
| | - Chih-Chi Andrew Hu
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, Texas, USA
| | - Adam B Glick
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, USA
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Galoian K, Dahl V, Perez A, Denny C, Becker B, Sedani A, Moran A, Martinez D, Hoyt A, Brown J. PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells. Cancer Treat Res Commun 2022; 33:100644. [PMID: 36368296 DOI: 10.1016/j.ctarc.2022.100644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/22/2022] [Accepted: 09/23/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells. MATERIALS AND METHODS Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1). RESULTS The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels. CONCLUSION PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.
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Affiliation(s)
- Karina Galoian
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Victoria Dahl
- University of Miami Miller School of Medicine, Miami, FL, United States
| | - Andres Perez
- University of Miami Miller School of Medicine, Miami, FL, United States
| | - Carina Denny
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States.
| | - Beatrice Becker
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Anil Sedani
- University of Miami Miller School of Medicine, Miami, FL, United States
| | - Alexandra Moran
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Daniel Martinez
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Aaron Hoyt
- Loyola University Medical Centre, Chicago, IL, United States
| | - Jeffrey Brown
- Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, United States
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47
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Rufo N, Yang Y, De Vleeschouwer S, Agostinis P. The "Yin and Yang" of Unfolded Protein Response in Cancer and Immunogenic Cell Death. Cells 2022; 11:2899. [PMID: 36139473 PMCID: PMC9497201 DOI: 10.3390/cells11182899] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/23/2022] Open
Abstract
Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging trait of cancer cells. Maladaptive UPR sustains oncogene-driven reprogramming of proteostasis and metabolism and fosters proinflammatory pathways promoting tissue repair and protumorigenic immune responses. However, when cancer cells are exposed to conditions causing irreparable ER homeostasis, such as those elicited by anticancer therapies, the UPR switches from a survival to a cell death program. This lethal ER stress response can elicit immunogenic cell death (ICD), a form of cell death with proinflammatory traits favoring antitumor immune responses. How UPR-driven pathways transit from a protective to a killing modality with favorable immunogenic and proinflammatory output remains unresolved. Here, we discuss key aspects of the functional dichotomy of UPR in cancer cells and how this signal can be harnessed for therapeutic benefit in the context of ICD, especially from the aspect of inflammation aroused by the UPR.
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Affiliation(s)
- Nicole Rufo
- Laboratory of Cell Death Research & Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
- VIB Center for Cancer Biology Research, 3000 Leuven, Belgium
| | - Yihan Yang
- Laboratory of Cell Death Research & Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
- VIB Center for Cancer Biology Research, 3000 Leuven, Belgium
- Research Group Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium
| | - Steven De Vleeschouwer
- Research Group Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium
- Department of Neurosurgery, University Hospitals Leuven, 3000 Leuven, Belgium
- Leuven Brain Institute (LBI), KU Leuven, 3000 Leuven, Belgium
| | - Patrizia Agostinis
- Laboratory of Cell Death Research & Therapy, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
- VIB Center for Cancer Biology Research, 3000 Leuven, Belgium
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48
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PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells. Sci Rep 2022; 12:13324. [PMID: 35922637 PMCID: PMC9349321 DOI: 10.1038/s41598-022-16909-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 07/18/2022] [Indexed: 11/16/2022] Open
Abstract
Retinal pigment epithelium (RPE) performs essential functions for ensuring retinal homeostasis and is a key site for pathogenic changes leading to age-related macular degeneration (AMD). Compromised proteostasis in RPE results in ER stress and ER stress-dependent antioxidant, apoptosis and autophagic responses. ER stress induces the unfolded protein response (UPR) in which EIF2AK3, encoding the protein kinase RNA-like ER kinase (PERK), acts as a key regulator. Downregulated EIF2AK3 gene expression has recently been identified in AMD using human donor RPE, however the molecular mechanisms that integrate the various ER-mediated cellular pathways underpinning progressive RPE dysfunction in AMD have not been fully characterised. This study investigated the downstream effects of PERK downregulation in response to Brefeldin A (BFA)-induced ER stress in ARPE-19 cells. PERK downregulation resulted in increased ER stress and impaired apoptosis induction, antioxidant responses and autophagic flux. ARPE-19 cells were unable to efficiently induce autophagy following PERK downregulation and PERK presented a role in regulating the rate of autophagy induction. The findings support PERK downregulation as an integrative event facilitating dysregulation of RPE processes critical to cell survival known to contribute to AMD development and highlight PERK as a potential future therapeutic target for AMD.
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49
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Wang F, Gu Y, Xu C, Du K, Zhao C, Zhao Y, Liu X. Transplantation of fecal microbiota from APP/PS1 mice and Alzheimer’s disease patients enhanced endoplasmic reticulum stress in the cerebral cortex of wild-type mice. Front Aging Neurosci 2022; 14:858130. [PMID: 35966768 PMCID: PMC9367971 DOI: 10.3389/fnagi.2022.858130] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/06/2022] [Indexed: 12/04/2022] Open
Abstract
Background and purpose The gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer’s disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown. Materials and methods In the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing. Results Excessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2α/eIF2α) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine-N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition. Conclusion The findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO.
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Affiliation(s)
- Fang Wang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Yongzhe Gu
- Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenhaoyi Xu
- Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kangshuai Du
- Shanghai Clinical College, Anhui Medical University, Hefei, China
| | - Chence Zhao
- School of Nursing, Medical College, Soochow University, Suzhou, China
| | - Yanxin Zhao
- Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Yanxin Zhao,
| | - Xueyuan Liu
- School of Clinical Medicine, Weifang Medical University, Weifang, China
- Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Xueyuan Liu,
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50
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Tao J, Srinivasan V, Yi X, Zhao Y, Zhang H, Lin X, Zhou X, Boyce BF, Villalta PW, Ebetino FH, Ho KK, Boeckman RK, Xing L. Bone-Targeted Bortezomib Inhibits Bortezomib-Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone. J Bone Miner Res 2022; 37:629-642. [PMID: 34970782 PMCID: PMC9018514 DOI: 10.1002/jbmr.4496] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 11/10/2022]
Abstract
Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone-residing cancer, especially drug-resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off-target effects. To this end, bone-targeted conjugate (BP-Btz) was generated by linking bortezomib (Btz, an anticancer, bone-stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Three conjugates with different linkers were developed and screened for best efficacy in mouse model of MM. Results demonstrated that the lead candidate BP-Btz with optimal linker could overcome Btz resistance, reduced tumor burden, bone destruction, or tumor metastasis more effectively than BP or free Btz without thrombocytopenia and neurotoxicity in mice bearing myeloma. Furthermore, pharmacokinetic and pharmacodynamic studies showed that BP-Btz bound to bone matrix, released Btz in acidic conditions, and had a higher local concentration and longer half-life than Btz in bone. Our findings suggest the potential of bone-targeted Btz conjugate as an efficacious Btz-resistant MM treatment mechanism. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Jianguo Tao
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Venkat Srinivasan
- Department of Chemistry, University of Rochester, Rochester, NY, USA
| | - Xiangjiao Yi
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Yingchun Zhao
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Hengwei Zhang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Xi Lin
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Xichao Zhou
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Brendan F Boyce
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.,Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Peter W Villalta
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Frank H Ebetino
- Department of Chemistry, University of Rochester, Rochester, NY, USA.,BioVinc, Pasadena, CA, USA
| | - Koc Kan Ho
- Ionova Life Science Co., Ltd, Shenzhen, China
| | - Robert K Boeckman
- Department of Chemistry, University of Rochester, Rochester, NY, USA
| | - Lianping Xing
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.,Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
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