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Dabsan S, Zur G, Abu-Freha N, Sofer S, Grossman-Haham I, Gilad A, Igbaria A. Cytosolic and endoplasmic reticulum chaperones inhibit wt-p53 to increase cancer cells' survival by refluxing ER-proteins to the cytosol. eLife 2025; 14:e102658. [PMID: 40202782 PMCID: PMC11981610 DOI: 10.7554/elife.102658] [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: 08/26/2024] [Accepted: 02/25/2025] [Indexed: 04/10/2025] Open
Abstract
The endoplasmic reticulum (ER) is an essential sensing organelle responsible for the folding and secretion of almost one-third of eukaryotic cells' total proteins. However, environmental, chemical, and genetic insults often lead to protein misfolding in the ER, accumulating misfolded proteins, and causing ER stress. To solve this, several mechanisms were reported to relieve ER stress by decreasing the ER protein load. Recently, we reported a novel ER surveillance mechanism by which proteins from the secretory pathway are refluxed to the cytosol to relieve the ER of its content. The refluxed proteins gain new prosurvival functions in cancer cells, thereby increasing cancer cell fitness. We termed this phenomenon ER to CYtosol Signaling (or 'ERCYS'). Here, we found that in mammalian cells, ERCYS is regulated by DNAJB12, DNAJB14, and the HSC70 cochaperone SGTA. Mechanistically, DNAJB12 and DNAJB14 bind HSC70 and SGTA - through their cytosolically localized J-domains to facilitate ER-protein reflux. DNAJB12 is necessary and sufficient to drive this phenomenon to increase AGR2 reflux and inhibit wt-p53 during ER stress. Mutations in DNAJB12/14 J-domain prevent the inhibitory interaction between AGR2-wt-p53. Thus, targeting the DNAJB12/14-HSC70/SGTA axis is a promising strategy to inhibit ERCYS and impair cancer cell fitness.
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Affiliation(s)
- Salam Dabsan
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
| | - Gali Zur
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
| | - Naim Abu-Freha
- Institute of Gastroenterology and Liver Diseases, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University of the NegevBeer ShevaIsrael
| | - Shahar Sofer
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
| | - Iris Grossman-Haham
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
- The Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the NegevBeer ShevaIsrael
| | - Ayelet Gilad
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
| | - Aeid Igbaria
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the NegevBeer ShevaIsrael
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2
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Zheng T, Huang KY, Tang XD, Wang FY, Lv L. Endoplasmic reticulum stress in gut inflammation: Implications for ulcerative colitis and Crohn's disease. World J Gastroenterol 2025; 31:104671. [PMID: 40248056 PMCID: PMC12001174 DOI: 10.3748/wjg.v31.i13.104671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/20/2025] [Accepted: 03/13/2025] [Indexed: 04/02/2025] Open
Abstract
Eukaryotic cells contain the endoplasmic reticulum (ER), a prevalent and intricate membranous structural system. During the development of inflammatory bowel disease (IBD), the stress on the ER and the start of the unfolded protein response are very important. Some chemicals, including 4μ8C, small molecule agonists of X-box binding protein 1, and ISRIB, work on the inositol-requiring enzyme 1, turn on transcription factor 6, and activate protein kinase RNA-like ER kinase pathways. This may help ease the symptoms of IBD. Researchers investigating the gut microbiota have discovered a correlation between ER stress and it. This suggests that changing the gut microbiota could help make new medicines for IBD. This study looks at how ER stress works and how it contributes to the emergence of IBD. It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.
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Affiliation(s)
- Ting Zheng
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Kai-Yue Huang
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xu-Dong Tang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feng-Yun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Lin Lv
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China
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3
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Dabsan S, Twito G, Biadsy S, Igbaria A. Less is better: various means to reduce protein load in the endoplasmic reticulum. FEBS J 2025; 292:976-989. [PMID: 38865586 PMCID: PMC11880973 DOI: 10.1111/febs.17201] [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: 12/27/2023] [Revised: 04/08/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024]
Abstract
The endoplasmic reticulum (ER) is an important organelle that controls the intracellular and extracellular environments. The ER is responsible for folding almost one-third of the total protein population in the eukaryotic cell. Disruption of ER-protein folding is associated with numerous human diseases, including metabolic disorders, neurodegenerative diseases, and cancer. During ER perturbations, the cells deploy various mechanisms to increase the ER-folding capacity and reduce ER-protein load by minimizing the number of substrates entering the ER to regain homeostasis. These mechanisms include signaling pathways, degradation mechanisms, and other processes that mediate the reflux of ER content to the cytosol. In this review, we will discuss the recent discoveries of five different ER quality control mechanisms, including the unfolded protein response (UPR), ER-associated-degradation (ERAD), pre-emptive quality control, ER-phagy and ER to cytosol signaling (ERCYS). We will discuss the roles of these processes in decreasing ER-protein load and inter-mechanism crosstalk.
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Affiliation(s)
- Salam Dabsan
- Department of Life SciencesBen‐Gurion University of the NegevBeer ShevaIsrael
| | - Gal Twito
- Department of Life SciencesBen‐Gurion University of the NegevBeer ShevaIsrael
| | - Suma Biadsy
- Department of Life SciencesBen‐Gurion University of the NegevBeer ShevaIsrael
| | - Aeid Igbaria
- Department of Life SciencesBen‐Gurion University of the NegevBeer ShevaIsrael
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4
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Vlahopoulos SA. Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin. Int J Mol Sci 2024; 25:8621. [PMID: 39201306 PMCID: PMC11354898 DOI: 10.3390/ijms25168621] [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: 07/10/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general.
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5
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Ma J, Yuan H, Zhang J, Sun X, Yi L, Li W, Li Z, Fu C, Zheng L, Xu X, Wang X, Wang F, Yin D, Yuan J, Xu C, Li Z, Peng X, Wang J. An ultrasound-activated nanoplatform remodels tumor microenvironment through diverse cell death induction for improved immunotherapy. J Control Release 2024; 370:501-515. [PMID: 38703950 DOI: 10.1016/j.jconrel.2024.05.001] [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: 12/02/2023] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials.
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Affiliation(s)
- Jingbo Ma
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Haitao Yuan
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Jingjing Zhang
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Xin Sun
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Letai Yi
- Inner Mongolia Medical University, Hohhot, PR China
| | - Weihua Li
- Medical Imaging Department, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, PR China
| | - Zhifen Li
- School of Chemistry and Chemical Engineering, Shanxi Datong University, Datong, Shanxi Province 037009, PR China
| | - Chunjin Fu
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Liuhai Zheng
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Xiaolong Xu
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Xiaoxian Wang
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Fujing Wang
- Department of Traditional Chinese Medicine, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Da Yin
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China
| | - Jimin Yuan
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China.
| | - Chengchao Xu
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; College of Integrative Medicine, Laboratory of Pathophysiology, Key Laboratory of Integrative Medicine on Chronic Diseases, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
| | - Zhijie Li
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China.
| | - Xin Peng
- Ningbo Municipal Hospital of TCM, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, China.
| | - Jigang Wang
- Department of Cardiology, Shenzhen Cardiovascular Minimally Invasive Medical Engineering Technology Research and Development Center, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, Guangdong, PR China; Department of Traditional Chinese Medicine, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PR China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, China; Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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6
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Obacz J, Archambeau J, Lafont E, Nivet M, Martin S, Aubry M, Voutetakis K, Pineau R, Boniface R, Sicari D, Pelizzari-Raymundo D, Ghukasyan G, McGrath E, Vlachavas EI, Le Gallo M, Le Reste PJ, Barroso K, Fainsod-Levi T, Obiedat A, Granot Z, Tirosh B, Samal J, Pandit A, Négroni L, Soriano N, Monnier A, Mosser J, Chatziioannou A, Quillien V, Chevet E, Avril T. IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma. Neuro Oncol 2024; 26:858-871. [PMID: 38153426 PMCID: PMC11066906 DOI: 10.1093/neuonc/noad256] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Intrinsic or environmental stresses trigger the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), leading to ER stress. To cope with this, cells have evolved an adaptive mechanism named the unfolded protein response (UPR) which is hijacked by tumor cells to develop malignant features. Glioblastoma (GB), the most aggressive and lethal primary brain tumor, relies on UPR to sustain growth. We recently showed that IRE1 alpha (referred to IRE1 hereafter), 1 of the UPR transducers, promotes GB invasion, angiogenesis, and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts a worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment toward monocytes/macrophages and neutrophils. METHODS We used human and mouse cellular models in which IRE1 was genetically or pharmacologically invalidated and which were tested in vivo. Publicly available datasets from GB patients were also analyzed to confirm our findings. RESULTS We showed that IRE1 signaling, through both the transcription factor XBP1s and the regulated IRE1-dependent decay controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, resulting in chemokine production and myeloid infiltration in tumors. CONCLUSIONS Our work identifies a novel IRE1/UBE2D3 proinflammatory axis that plays an instrumental role in GB immune regulation.
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Affiliation(s)
- Joanna Obacz
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | | | - Elodie Lafont
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | - Manon Nivet
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | - Sophie Martin
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | | | | | - Raphael Pineau
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | | | - Daria Sicari
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | | | | | - Eoghan McGrath
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | | | | | - Pierre Jean Le Reste
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
- Hospital of St Malo, France
| | - Kim Barroso
- IGBMC, Illkirch, France
- CNRS UMR7104, Illkirch, France
- INSERM U1258, Illkirch, France
| | - Tanya Fainsod-Levi
- Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Israel
| | | | - Zvi Granot
- Department of Developmental Biology and Cancer Research, Hebrew University of Jerusalem, Israel
| | | | | | | | - Luc Négroni
- IGBMC, Illkirch, France
- CNRS UMR7104, Illkirch, France
- INSERM U1258, Illkirch, France
| | | | | | | | - Aristotelis Chatziioannou
- ICB, NHRF, Athens, Greece
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Eric Chevet
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
| | - Tony Avril
- INSERM U1242, Rennes, France
- Centre Eugène Marquis, Rennes, France
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7
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Bartoszewska S, Sławski J, Collawn JF, Bartoszewski R. Dual RNase activity of IRE1 as a target for anticancer therapies. J Cell Commun Signal 2023:10.1007/s12079-023-00784-5. [PMID: 37721642 DOI: 10.1007/s12079-023-00784-5] [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: 02/01/2023] [Accepted: 08/31/2023] [Indexed: 09/19/2023] Open
Abstract
The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic.
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Affiliation(s)
- Sylwia Bartoszewska
- Department of Inorganic Chemistry, Medical University of Gdansk, Gdansk, Poland
| | - Jakub Sławski
- Department of Biophysics, Faculty of Biotechnology, University of Wrocław, F. Joliot-Curie 14a Street, 50-383, Wrocław, Poland
| | - James F Collawn
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Rafał Bartoszewski
- Department of Biophysics, Faculty of Biotechnology, University of Wrocław, F. Joliot-Curie 14a Street, 50-383, Wrocław, Poland.
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8
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Li L, Tan H, Zhou J, Hu F. Predicting response of immunotherapy and targeted therapy and prognosis characteristics for renal clear cell carcinoma based on m1A methylation regulators. Sci Rep 2023; 13:12645. [PMID: 37542141 PMCID: PMC10403615 DOI: 10.1038/s41598-023-39935-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 08/02/2023] [Indexed: 08/06/2023] Open
Abstract
In recent years, RNA methylation modification has been found to be related to a variety of tumor mechanisms, such as rectal cancer. Clear cell renal cell carcinoma (ccRCC) is most common in renal cell carcinoma. In this study, we get the RNA profiles of ccRCC patients from ArrayExpress and TCGA databases. The prognosis model of ccRCC was developed by the least absolute shrinkage and selection operator (LASSO) regression analysis, and the samples were stratified into low-high risk groups. In addition, our prognostic model was validated through the receiver operating characteristic curve (ROC). "pRRophetic" package screened five potential small molecule drugs. Protein interaction networks explore tumor driving factors and drug targeting factors. Finally, polymerase chain reaction (PCR) was used to verify the expression of the model in the ccRCC cell line. The mRNA matrix in ArrayExpress and TCGA databases was used to establish a prognostic model for ccRCC through LASSO regression analysis. Kaplan Meier analysis showed that the overall survival rate (OS) of the high-risk group was poor. ROC verifies the reliability of our model. Functional enrichment analysis showed that there was a obviously difference in immune status between the high-low risk groups. "pRRophetic" package screened five potential small molecule drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706). Protein interaction network shows that epidermal growth factor receptor [EGRF] and estrogen receptor 1 [ESR1] are tumor drivers and drug targeting factors. To further analyze the differential expression and pathway correlation of the prognosis risk model species. Finally, polymerase chain reaction (PCR) showed the expression of YTHN6-Methyladenosine RNA Binding Protein 1[YTHDF1], TRNA Methyltransferase 61B [TRMT61B], TRNA Methyltransferase 10C [TRMT10C] and AlkB Homolog 1[ALKBH1] in ccRCC cell lines. To sum up, the prognosis risk model we created not only has good predictive value, but also can provide guidance for accurately predicting the prognosis of ccRCC.
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Affiliation(s)
- Lei Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Hongwei Tan
- Department of Organ Transplantation, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, People's Republic of China
| | - Jiexue Zhou
- Department of Organ Transplantation, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, People's Republic of China.
| | - Fengming Hu
- Department of Organ Transplantation, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, People's Republic of China.
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9
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Izadpanah A, Willingham K, Chandrasekar B, Alt EU, Izadpanah R. Unfolded protein response and angiogenesis in malignancies. Biochim Biophys Acta Rev Cancer 2023; 1878:188839. [PMID: 36414127 PMCID: PMC10167724 DOI: 10.1016/j.bbcan.2022.188839] [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: 08/19/2022] [Revised: 11/08/2022] [Accepted: 11/12/2022] [Indexed: 11/21/2022]
Abstract
Cellular stress, arising from accumulation of unfolded proteins, occurs frequently in rapidly proliferating cancer cells. This cellular stress, in turn, activates the unfolded protein response (UPR), an interconnected set of signal transduction pathways that alleviate the proteostatic stress. The UPR is implicated in cancer cell survival and proliferation through upregulation of pro-tumorigenic pathways that ultimately promote malignant metabolism and neoangiogenesis. Here, we reviewed mechanisms of signaling crosstalk between the UPR and angiogenesis pathways, as well as transmissible ER stress and the role in tumor growth and development. To characterize differences in UPR and UPR-mediated angiogenesis in malignancy, we employed a data mining approach using patient tumor data from The Cancer Genome Atlas (TCGA). The analysis of TCGA revealed differences in UPR between malignant samples versus their non-malignant counterparts.
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Affiliation(s)
- Amin Izadpanah
- Applied Stem Cell Laboratory, Department of Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA
| | - Kurtis Willingham
- Applied Stem Cell Laboratory, Department of Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bysani Chandrasekar
- Department of Medicine, University of Missouri School of Medicine and Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA
| | - Eckhard U Alt
- Applied Stem Cell Laboratory, Department of Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Reza Izadpanah
- Applied Stem Cell Laboratory, Department of Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA; Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
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10
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Pavlović N, Heindryckx F. Targeting ER stress in the hepatic tumor microenvironment. FEBS J 2022; 289:7163-7176. [PMID: 34331743 DOI: 10.1111/febs.16145] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala University, Sweden
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11
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Pancreatic ductal adenocarcinoma: tumor microenvironment and problems in the development of novel therapeutic strategies. Clin Exp Med 2022:10.1007/s10238-022-00886-1. [DOI: 10.1007/s10238-022-00886-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/30/2022] [Indexed: 12/19/2022]
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12
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Wang Z, Jiao P, Zhong Y, Ji H, Zhang Y, Song H, Du H, Ding X, Wu H. The Endoplasmic Reticulum-Stressed Head and Neck Squamous Cell Carcinoma Cells Induced Exosomal miR-424-5p Inhibits Angiogenesis and Migration of Humanumbilical Vein Endothelial Cells Through LAMC1-Mediated Wnt/β-Catenin Signaling Pathway. Cell Transplant 2022; 31:9636897221083549. [PMID: 35315295 PMCID: PMC8943634 DOI: 10.1177/09636897221083549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Under endoplasmic reticulum (ER) stress, tumor plays multifaceted roles in
endothelial cell dysfunction through secreting exosomal miRNAs. However, for the
head and neck squamous cell carcinoma (HNSCC), it is still unclear about the
impact of ER-stressed HNSCC cell derived exosomes on vascular endothelial cells.
To address this gap, herein, systemic research was conducted including isolation
and characterization of ER-stressed HNSCC cell (HN4 cell line as an in
vitro model) derived exosomes, identification of regulatory
exosomal miRNAs, target exploration and downstream signaling pathway
investigation of exosomal miRNAs in human umbilical vein endothelial cell
(HUVEC). ER-stressed HN4 cell-derived exosomes inhibited angiogenesis and
migration of HUVEC cells in vitro. Furthermore, RNA-seq
analysis demonstrated that miR-424-5p was highly upregulated in ER-stressed HN4
cell-derived exosomes. Through matrigel tube formation and transwell assays of
HUVEC cells, miR-424-5p displayed great capabilities on inhibiting angiogenesis
and migration. Finally, based on western blot and luciferase reporter, it was
demonstrated that LAMC1 is the target of miR-424-5p which could inhibit the
angiogenesis and migration of HUVEC cells by repressing the LAMC1-mediated
Wnt/β-catenin signaling pathway. ER-stressed HNSCC cell-induced exosomal
miR-424-5p inhibits angiogenesis and migration of HUVEC cells through
LAMC1-mediated Wnt/β-catenin signaling pathway. This study offers a new insight
for understanding the complicated mechanism behind ER-stress induced
anti-angiogenesis of HNSCC.
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Affiliation(s)
- Zeyu Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Pengfei Jiao
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Yi Zhong
- Department of General Dentistry, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Huan Ji
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.,Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China
| | - Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Haiyang Song
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, China.,Department of General Dentistry, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Hongming Du
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Xu Ding
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
| | - Heming Wu
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
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13
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Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov 2021; 21:115-140. [PMID: 34702991 DOI: 10.1038/s41573-021-00320-3] [Citation(s) in RCA: 282] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2021] [Indexed: 02/08/2023]
Abstract
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, resulting in activation of the unfolded protein response (UPR) that aims to restore protein homeostasis. However, the UPR also plays an important pathological role in many diseases, including metabolic disorders, cancer and neurological disorders. Over the last decade, significant effort has been invested in targeting signalling proteins involved in the UPR and an array of drug-like molecules is now available. However, these molecules have limitations, the understanding of which is crucial for their development into therapies. Here, we critically review the existing ER stress and UPR-directed drug-like molecules, highlighting both their value and their limitations.
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14
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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Hargreaves A, Barry ST, Bigley A, Kendrew J, Price S. Tumors modulate fenestrated vascular beds and host endocrine status. J Appl Toxicol 2021; 41:1952-1965. [PMID: 33977518 DOI: 10.1002/jat.4176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 11/12/2022]
Abstract
Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.
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16
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Unraveling the Molecular Nexus between GPCRs, ERS, and EMT. Mediators Inflamm 2021; 2021:6655417. [PMID: 33746610 PMCID: PMC7943314 DOI: 10.1155/2021/6655417] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.
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Fu X, Cui J, Meng X, Jiang P, Zheng Q, Zhao W, Chen X. Endoplasmic reticulum stress, cell death and tumor: Association between endoplasmic reticulum stress and the apoptosis pathway in tumors (Review). Oncol Rep 2021; 45:801-808. [PMID: 33469681 PMCID: PMC7859917 DOI: 10.3892/or.2021.7933] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023] Open
Abstract
External and internal stimuli are often involved in the pathogenesis of tumors, and the deterioration of endoplasmic reticulum (ER) function within cells is also an important etiological factor of tumorigenesis resulting in the impairment of the endoplasmic reticulum, which is termed ER stress. The ER is an organelle that serves a crucial role in the process of protein synthesis and maturation, and also acts as a reservoir of calcium to maintain intracellular Ca2+ homeostasis. ER stress has been revealed to serve a critical role in tumorigenesis. In the present review, the association between ER stress‑related pathways and tumor cell apoptosis is examined. Primarily, the role of ER stress in tumor cell apoptosis is discussed, and it is stipulated that ER stress, induced by drugs both directly and indirectly, promotes tumor cell apoptosis.
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Affiliation(s)
- Xiaojing Fu
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Juanjuan Cui
- Qingdao Municipal Hospital, Qingdao (Group), Qingdao, Shandong 266071, P.R. China
| | - Xiangjun Meng
- Qingdao Mental Health Center, Qingdao, Shandong 266071, P.R. China
| | - Piyu Jiang
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Qiuling Zheng
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wenwen Zhao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuehong Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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Ma RH, Ni ZJ, Thakur K, Zhang F, Zhang YY, Zhang JG, Wei ZJ. Natural Compounds Play Therapeutic Roles in Various Human Pathologies via Regulating Endoplasmic Reticulum Pathway. MEDICINE IN DRUG DISCOVERY 2020. [DOI: 10.1016/j.medidd.2020.100065] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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19
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Alhammad R, Khunchai S, Tongmuang N, Limjindaporn T, Yenchitsomanus PT, Mutti L, Krstic-Demonacos M, Demonacos C. Protein disulfide isomerase A1 regulates breast cancer cell immunorecognition in a manner dependent on redox state. Oncol Rep 2020; 44:2406-2418. [PMID: 33125139 PMCID: PMC7610313 DOI: 10.3892/or.2020.7816] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/01/2020] [Indexed: 12/21/2022] Open
Abstract
Oxidoreductase protein disulphide isomerases (PDI) are involved in the regulation of a variety of biological processes including the modulation of endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER-mitochondria communication and the balance between pro-survival and pro-death pathways. In the current study the role of the PDIA1 family member in breast carcinogenesis was investigated by measuring ROS generation, mitochondrial membrane disruption, ATP production and HLA-G protein levels on the surface of the cellular membrane in the presence or absence of PDIA1. The results showed that this enzyme exerted pro-apoptotic effects in estrogen receptor (ERα)-positive breast cancer MCF-7 and pro-survival in triple negative breast cancer (TNBC) MDA-MB-231 cells. ATP generation was upregulated in PDIA1-silenced MCF-7 cells and downregulated in PDIA1-silenced MDA-MB-231 cells in a manner dependent on the cellular redox status. Furthermore, MCF-7 and MDA-MB-231 cells in the presence of PDIA1 expressed higher surface levels of the non-classical human leukocyte antigen (HLA-G) under oxidative stress conditions. Evaluation of the METABRIC datasets showed that low PDIA1 and high HLA-G mRNA expression levels correlated with longer survival in both ERα-positive and ERα-negative stage 2 breast cancer patients. In addition, analysis of the PDIA1 vs. the HLA-G mRNA ratio in the subgroup of the living stage 2 breast cancer patients exhibiting low PDIA1 and high HLA-G mRNA levels revealed that the longer the survival time of the ratio was high PDIA1 and low HLA-G mRNA and occurred predominantly in ERα-positive breast cancer patients whereas in the same subgroup of the ERα-negative breast cancer mainly this ratio was low PDIA1 and high HLA-G mRNA. Taken together these results provide evidence supporting the view that PDIA1 is linked to several hallmarks of breast cancer pathways including the process of antigen processing and presentation and tumor immunorecognition.
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Affiliation(s)
- Rashed Alhammad
- Faculty of Biology Medicine and Health, School of Health Sciences, Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PT, UK
| | - Sasiprapa Khunchai
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
| | - Nopprarat Tongmuang
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Thawornchai Limjindaporn
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pa-Thai Yenchitsomanus
- Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Luciano Mutti
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
| | | | - Constantinos Demonacos
- Faculty of Biology Medicine and Health, School of Health Sciences, Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PT, UK
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20
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Díaz MI, Díaz P, Bennett JC, Urra H, Ortiz R, Orellana PC, Hetz C, Quest AFG. Caveolin-1 suppresses tumor formation through the inhibition of the unfolded protein response. Cell Death Dis 2020; 11:648. [PMID: 32811828 PMCID: PMC7434918 DOI: 10.1038/s41419-020-02792-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
Caveolin-1 (CAV1), is a broadly expressed, membrane-associated scaffolding protein that acts both, as a tumor suppressor and a promoter of metastasis, depending on the type of cancer and stage. CAV1 is downregulated in human tumors, tumor cell lines and oncogene-transformed cells. The tumor suppressor activity of CAV1 is generally associated with its presence at the plasma membrane, where it participates, together with cavins, in the formation of caveolae and also has been suggested to interact with and inhibit a wide variety of proteins through interactions mediated by the scaffolding domain. However, a pool of CAV1 is also located at the endoplasmic reticulum (ER), modulating the secretory pathway in a manner dependent on serine-80 (S80) phosphorylation. In melanoma cells, CAV1 expression suppresses tumor formation, but the protein is largely absent from the plasma membrane and does not form caveolae. Perturbations to the function of the ER are emerging as a central driver of cancer, highlighting the activation of the unfolded protein response (UPR), a central pathway involved in stress mitigation. Here we provide evidence indicating that the expression of CAV1 represses the activation of the UPR in vitro and in solid tumors, reflected in the attenuation of PERK and IRE1α signaling. These effects correlated with increased susceptibility of cells to ER stress and hypoxia. Interestingly, the tumor suppressor activity of CAV1 was abrogated by site-directed mutagenesis of S80, correlating with a reduced ability to repress the UPR. We conclude that the tumor suppression by CAV1 involves the attenuation of the UPR, and identified S80 as essential in this context. This suggests that intracellular CAV1 regulates cancer through alternative signaling outputs.
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Affiliation(s)
- María I Díaz
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile
| | - Paula Díaz
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
| | - Jimena Castillo Bennett
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
| | - Hery Urra
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile
- FONDAP Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Laboratory of Proteostasis Control and Biomedicine, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Rina Ortiz
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile
| | - Pamela Contreras Orellana
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile.
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile.
- FONDAP Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile.
- Laboratory of Proteostasis Control and Biomedicine, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
- Buck Institute for Research on Aging, Novato, CA, 94945, USA.
| | - Andrew F G Quest
- Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile.
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago, Chile.
- Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile.
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IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells. Biomolecules 2020; 10:biom10060895. [PMID: 32545307 PMCID: PMC7355874 DOI: 10.3390/biom10060895] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/06/2020] [Accepted: 06/07/2020] [Indexed: 12/12/2022] Open
Abstract
While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.
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22
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Lafont E. Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer. Cancers (Basel) 2020; 12:E1113. [PMID: 32365592 PMCID: PMC7281445 DOI: 10.3390/cancers12051113] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
Throughout tumour progression, tumour cells are exposed to various intense cellular stress conditions owing to intrinsic and extrinsic cues, to which some cells are remarkably able to adapt. Death Receptor (DR) signalling and the Unfolded Protein Response (UPR) are two stress responses that both regulate a plethora of outcomes, ranging from proliferation, differentiation, migration, cytokine production to the induction of cell death. Both signallings are major modulators of physiological tissue homeostasis and their dysregulation is involved in tumorigenesis and the metastastic process. The molecular determinants of the control between the different cellular outcomes induced by DR signalling and the UPR in tumour cells and their stroma and their consequences on tumorigenesis are starting to be unravelled. Herein, I summarize the main steps of DR signalling in relation to its cellular and pathophysiological roles in cancer. I then highlight how the UPR and DR signalling control common cellular outcomes and also cross-talk, providing potential opportunities to further understand the development of malignancies.
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Affiliation(s)
- Elodie Lafont
- Inserm U1242, Université de Rennes, 35042 Rennes, France;
- Centre de Lutte Contre le Cancer Eugène Marquis, 35042 Rennes, France
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Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells. Proc Natl Acad Sci U S A 2020; 117:9932-9941. [PMID: 32312819 PMCID: PMC7211964 DOI: 10.1073/pnas.1913707117] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
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24
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The Role of HSF1 and the Chaperone Network in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1243:101-111. [PMID: 32297214 DOI: 10.1007/978-3-030-40204-4_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Tumors are stressful environments. As tumors evolve from single mutated cancer cells into invasive malignancies they must overcome various constraints and barriers imposed by a hostile microenvironment. To achieve this, cancer cells recruit and rewire cells in their microenvironment to become pro-tumorigenic. We propose that chaperones are vital players in this process, and that activation of stress responses helps tumors adapt and evolve into aggressive malignancies, by enabling phenotypic plasticity in the tumor microenvironment (TME). In this chapter we will review evidence supporting non-cancer-cell-autonomous activity of chaperones in human patients and mouse models of cancer, discuss the mechanisms by which this non-cell-autonomous activity is mediated and provide an evolutionary perspective on the basis of this phenomenon.
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Soriani O, Kourrich S. The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer. Front Neurosci 2019; 13:1186. [PMID: 31780884 PMCID: PMC6861184 DOI: 10.3389/fnins.2019.01186] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022] Open
Abstract
The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.
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Affiliation(s)
| | - Saïd Kourrich
- Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC, Canada.,Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Montréal, Montréal, QC, Canada.,Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
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Marciniak SJ. Endoplasmic reticulum stress: a key player in human disease. FEBS J 2019; 286:228-231. [PMID: 30677245 DOI: 10.1111/febs.14740] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 12/28/2022]
Abstract
This Special Issue comprises eleven excellent reviews that illustrate the role of ER stress in different human diseases, including myopathies and lung diseases, as well as in modulating liver dysfunction and inflammatory responses. These reviews also highlight the function of the UPR in neurodegenerative disorders and cancer, while discussing the potential benefits of targeting the UPR as a therapeutic approach. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions.
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Affiliation(s)
- Stefan J Marciniak
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK
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Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion. Cancers (Basel) 2019; 11:cancers11050631. [PMID: 31064137 PMCID: PMC6562633 DOI: 10.3390/cancers11050631] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/29/2019] [Accepted: 05/01/2019] [Indexed: 12/21/2022] Open
Abstract
Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion.
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Novel Curcumin Inspired Bis-Chalcone Promotes Endoplasmic Reticulum Stress and Glioblastoma Neurosphere Cell Death. Cancers (Basel) 2019; 11:cancers11030357. [PMID: 30871215 PMCID: PMC6468769 DOI: 10.3390/cancers11030357] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/04/2019] [Accepted: 03/07/2019] [Indexed: 01/11/2023] Open
Abstract
Glioblastoma (GBM) has a dismal prognosis and successful elimination of GBM stem cells (GSCs) is a high-priority as these cells are responsible for tumor regrowth following therapy and ultimately patient relapse. Natural products and their derivatives continue to be a source for the development of effective anticancer drugs and have been shown to effectively target pathways necessary for cancer stem cell self-renewal and proliferation. We generated a series of curcumin inspired bis-chalcones and examined their effect in multiple patient-derived GSC lines. Of the 19 compounds synthesized, four analogs robustly induced GSC death in six separate GSC lines, with a half maximal inhibitory concentration (IC50) ranging from 2.7–5.8 μM and significantly reduced GSC neurosphere formation at sub-cytotoxic levels. Structural analysis indicated that the presence of a methoxy group at position 3 of the lateral phenylic appendages was important for activity. Pathway and drug connectivity analysis of gene expression changes in response to treatment with the most active bis-chalcone 4j (the 3,4,5 trimethoxy substituted analog) suggested that the mechanism of action was the induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) mediated cell death. This was confirmed by Western blot analysis in which 4j induced robust increases in CHOP, p-jun and caspase 12. The UPR is believed to play a significant role in GBM pathogenesis and resistance to therapy and as such represents a promising therapeutic target.
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Dickens JA, Malzer E, Chambers JE, Marciniak SJ. Pulmonary endoplasmic reticulum stress-scars, smoke, and suffocation. FEBS J 2019; 286:322-341. [PMID: 29323786 DOI: 10.1111/febs.14381] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/11/2017] [Accepted: 01/08/2018] [Indexed: 12/14/2022]
Abstract
Protein misfolding within the endoplasmic reticulum (ER stress) can be a cause or consequence of pulmonary disease. Mutation of proteins restricted to the alveolar type II pneumocyte can lead to inherited forms of pulmonary fibrosis, but even sporadic cases of pulmonary fibrosis appear to be strongly associated with activation of the unfolded protein response and/or the integrated stress response. Inhalation of smoke can impair protein folding and may be an important cause of pulmonary ER stress. Similarly, tissue hypoxia can lead to impaired protein homeostasis (proteostasis). But the mechanisms linking smoke and hypoxia to ER stress are only partially understood. In this review, we will examine the role of ER stress in the pathogenesis of lung disease by focusing on fibrosis, smoke, and hypoxia.
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Affiliation(s)
- Jennifer A Dickens
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK
| | - Elke Malzer
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK
| | - Joseph E Chambers
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK
| | - Stefan J Marciniak
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK
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Asha K, Sharma-Walia N. Virus and tumor microenvironment induced ER stress and unfolded protein response: from complexity to therapeutics. Oncotarget 2018; 9:31920-31936. [PMID: 30159133 PMCID: PMC6112759 DOI: 10.18632/oncotarget.25886] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/21/2018] [Indexed: 12/28/2022] Open
Abstract
Endoplasmic reticulum (ER) stress can be activated by various pathological and physiological conditions including the unfolded protein response (UPR) to restore homeostasis. The UPR signaling pathways initiated by double-stranded RNA-activated protein kinase (PKR) like ER kinase (PERK), inositol requiring enzyme 1 α (IRE1α), and activating transcription factor 6 (ATF6) are vital for tumor growth, aggressiveness, microenvironment remodeling, and resistance to cancer therapeutics. This review focuses on the role of ER stress and activity of UPR signaling pathways involved in tumor formation and uncontrolled cell proliferation during various cancers and viral malignancies.
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Affiliation(s)
- Kumari Asha
- Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
| | - Neelam Sharma-Walia
- Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, U.S.A
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Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils. Proc Natl Acad Sci U S A 2018; 115:E2202-E2209. [PMID: 29463754 DOI: 10.1073/pnas.1717439115] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use.
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