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Balamurli G, Liew AQX, Tee WW, Pervaiz S. Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications. Redox Biol 2024; 78:103441. [PMID: 39612910 PMCID: PMC11629570 DOI: 10.1016/j.redox.2024.103441] [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: 10/29/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.
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Affiliation(s)
- Geoffrey Balamurli
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Angeline Qiu Xia Liew
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore
| | - Wee Wei Tee
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Chromatin Dynamics and Disease Epigenetics Lab, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore; Integrative Science and Engineering Programme (ISEP), NUS Graduate School (NUSGS), NUS, Singapore; NUS Medicine Healthy Longevity Program, NUS, Singapore; National University Cancer Institute, National University Health System, Singapore.
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2
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Mackova V, Raudenska M, Polanska HH, Jakubek M, Masarik M. Navigating the redox landscape: reactive oxygen species in regulation of cell cycle. Redox Rep 2024; 29:2371173. [PMID: 38972297 PMCID: PMC11637001 DOI: 10.1080/13510002.2024.2371173] [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] [Indexed: 07/09/2024] Open
Abstract
Objectives: To advance our knowledge of disease mechanisms and therapeutic options, understanding cell cycle regulation is critical. Recent research has highlighted the importance of reactive oxygen species (ROS) in cell cycle regulation. Although excessive ROS levels can lead to age-related pathologies, ROS also play an essential role in normal cellular functions. Many cell cycle regulatory proteins are affected by their redox status, but the precise mechanisms and conditions under which ROS promote or inhibit cell proliferation are not fully understood.Methods: This review presents data from the scientific literature and publicly available databases on changes in redox state during the cell cycle and their effects on key regulatory proteins.Results: We identified redox-sensitive targets within the cell cycle machinery and analysed different effects of ROS (type, concentration, duration of exposure) on cell cycle phases. For example, moderate levels of ROS can promote cell proliferation by activating signalling pathways involved in cell cycle progression, whereas excessive ROS levels can induce DNA damage and trigger cell cycle arrest or cell death.Discussion: Our findings encourage future research focused on identifying redox-sensitive targets in the cell cycle machinery, potentially leading to new treatments for diseases with dysregulated cell proliferation.
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Affiliation(s)
- Viktoria Mackova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Martina Raudenska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Hana Holcova Polanska
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
| | - Michal Masarik
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
- Institute of Pathophysiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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3
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McGee SL, Hargreaves M. Exercise performance and health: Role of GLUT4. Free Radic Biol Med 2024; 224:479-483. [PMID: 39243828 DOI: 10.1016/j.freeradbiomed.2024.09.004] [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: 06/04/2024] [Revised: 08/20/2024] [Accepted: 09/01/2024] [Indexed: 09/09/2024]
Abstract
The glucose transporter GLUT4 is integral for optimal skeletal muscle performance during exercise, as well as for metabolic health. Physiological regulation of GLUT4 translocation during exercise and increased GLUT4 expression following exercise involves multiple, redundant signalling pathways. These include effects of reactive oxygen species (ROS). ROS contribute to GLUT4 translocation that increases skeletal muscle glucose uptake during exercise and stimulate signalling pathways that increase GLUT4 expression. Conversely, ROS can also inhibit GLUT4 translocation and expression in metabolic disease states. The opposing roles of ROS in GLUT4 regulation are ultimately linked to the metabolic state of skeletal muscle and the intricate mechanisms involved give insights into pathways critical for exercise performance and implicated in metabolic health and disease.
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Affiliation(s)
- Sean L McGee
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Waurn Ponds, 3217, Australia.
| | - Mark Hargreaves
- Department of Anatomy & Physiology, University of Melbourne, 3010, Australia.
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4
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Kukulage DSK, Samarasinghe KTG, Matarage Don NNJ, Shivamadhu MC, Shishikura K, Schiff W, Mashhadi Ramezani F, Padmavathi R, Matthews ML, Ahn YH. Protein phosphatase PP2Cα S-glutathionylation regulates cell migration. J Biol Chem 2024; 300:107784. [PMID: 39303918 PMCID: PMC11530597 DOI: 10.1016/j.jbc.2024.107784] [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: 05/18/2024] [Revised: 08/07/2024] [Accepted: 08/29/2024] [Indexed: 09/22/2024] Open
Abstract
Redox signaling is a fundamental mechanism that controls all major biological processes partly via protein cysteine oxidations, including S-glutathionylation. Despite over 2000 cysteines identified to form S-glutathionylation in databases, the identification of redox cysteines functionally linked to a biological process of interest remains challenging. Here, we demonstrate a strategy combining glutathionylation proteomic database, bioinformatics, and biological screening, which resulted in the identification of S-glutathionylated proteins, including PP2Cα, as redox players of cell migration. We showed that PP2Cα, a prototypical magnesium-dependent serine/threonine phosphatase, is susceptible to S-glutathionylation selectively at nonconserved C314. PP2Cα glutathionylation causes increased migration and invasion of breast cancer cell lines in oxidative stress or upon hydrogen peroxide production. Mechanistically, PP2Cα glutathionylation modulates its protein-protein interactions, activating c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways to elevate migration and invasion. In addition, PP2Cα glutathionylation occurs in response to epidermal growth factor, supporting a serine/threonine phosphatase PP2Cα as a new redox player in growth factor signal transduction.
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Affiliation(s)
| | | | | | - Madhu C Shivamadhu
- Department of Chemistry, Drexel University, Philadelphia, Pennsylvania, USA
| | - Kyosuke Shishikura
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - William Schiff
- Department of Chemistry, Drexel University, Philadelphia, Pennsylvania, USA
| | | | | | - Megan L Matthews
- Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Young-Hoon Ahn
- Department of Chemistry, Drexel University, Philadelphia, Pennsylvania, USA.
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5
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Ulfig A, Jakob U. Cellular oxidants and the proteostasis network: balance between activation and destruction. Trends Biochem Sci 2024; 49:761-774. [PMID: 39168791 PMCID: PMC11731897 DOI: 10.1016/j.tibs.2024.07.001] [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: 06/27/2024] [Accepted: 07/09/2024] [Indexed: 08/23/2024]
Abstract
Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation. While reactive oxygen species (ROS) were traditionally considered culprits in this process, recent research challenges this view. While harmful at high concentrations, moderate ROS levels protect the cell against age-mediated onset of proteotoxicity by activating molecular chaperones, stress response pathways, and autophagy. This review explores the nuanced roles of ROS in proteostasis and discusses the most recent findings regarding the redox regulation of the PN and its potential in extending healthspan and delaying age-related pathologies.
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Affiliation(s)
- Agnes Ulfig
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Ursula Jakob
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Biological Chemistry Department, University of Michigan Medical School, Ann Arbor, MI, USA.
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6
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Lee ZY, Lee WH, Lim JS, Ali AAA, Loo JSE, Wibowo A, Mohammat MF, Foo JB. Golgi apparatus targeted therapy in cancer: Are we there yet? Life Sci 2024; 352:122868. [PMID: 38936604 DOI: 10.1016/j.lfs.2024.122868] [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: 01/24/2024] [Revised: 06/14/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024]
Abstract
Membrane trafficking within the Golgi apparatus plays a pivotal role in the intracellular transportation of lipids and proteins. Dysregulation of this process can give rise to various pathological manifestations, including cancer. Exploiting Golgi defects, cancer cells capitalise on aberrant membrane trafficking to facilitate signal transduction, proliferation, invasion, immune modulation, angiogenesis, and metastasis. Despite the identification of several molecular signalling pathways associated with Golgi abnormalities, there remains a lack of approved drugs specifically targeting cancer cells through the manipulation of the Golgi apparatus. In the initial section of this comprehensive review, the focus is directed towards delineating the abnormal Golgi genes and proteins implicated in carcinogenesis. Subsequently, a thorough examination is conducted on the impact of these variations on Golgi function, encompassing aspects such as vesicular trafficking, glycosylation, autophagy, oxidative mechanisms, and pH alterations. Lastly, the review provides a current update on promising Golgi apparatus-targeted inhibitors undergoing preclinical and/or clinical trials, offering insights into their potential as therapeutic interventions. Significantly more effort is required to advance these potential inhibitors to benefit patients in clinical settings.
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Affiliation(s)
- Zheng Yang Lee
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Wen Hwei Lee
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Jing Sheng Lim
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Afiqah Ali Ajmel Ali
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia
| | - Jason Siau Ee Loo
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia; Digital Health and Medical Advancements Impact Lab, Taylor's University, Subang Jaya 47500, Selangor, Malaysia
| | - Agustono Wibowo
- Faculty of Applied Science, Universiti Teknologi MARA (UiTM) Pahang, Jengka Campus, 26400 Bandar Tun Abdul Razak Jengka, Pahang, Malaysia
| | - Mohd Fazli Mohammat
- Organic Synthesis Laboratory, Institute of Science, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor, Malaysia
| | - Jhi Biau Foo
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia; Digital Health and Medical Advancements Impact Lab, Taylor's University, Subang Jaya 47500, Selangor, Malaysia
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7
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Huang G, Liu J, Yu A, Luo C, Zhu J, Wang Y, Dai Z, Zhang L, Feng Z, Lu J, Dong Z, Luo J, Chen W, Chen Z. Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer. Cell Mol Life Sci 2024; 81:292. [PMID: 38976080 PMCID: PMC11335216 DOI: 10.1007/s00018-024-05320-1] [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: 02/13/2024] [Revised: 06/11/2024] [Accepted: 06/13/2024] [Indexed: 07/09/2024]
Abstract
Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What's more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.
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Affiliation(s)
- Gaowei Huang
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- Department of Urology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China
| | - Jinwen Liu
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Anze Yu
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Chenggong Luo
- Department of Urology, Guizhou Provincial People's Hospital, Guizhou University, Guiyang, 550002, China
| | - Jiangquan Zhu
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yinghan Wang
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ziran Dai
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Lizhen Zhang
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zihao Feng
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jun Lu
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhong Dong
- Department of Urology, Huizhou Central People's Hospital, Huizhou, 516001, China.
| | - Junhang Luo
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Wei Chen
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Zhenhua Chen
- Department of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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8
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Xu H, Cai Y, Yang H, Li S, Chen P, Wei Z, Wang F, Wang Z, Zhang Y. PPP2R2A promotes Hu sheep pituitary cell proliferation and gonadotropin secretion associated with prolificacy. Anim Reprod Sci 2024; 265:107457. [PMID: 38677100 DOI: 10.1016/j.anireprosci.2024.107457] [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: 01/02/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/29/2024]
Abstract
The anterior pituitary plays a critical role in the endocrine system, contains gonadotrophs, which regulate reproductive efficiency by secreting follicle-stimulating hormone (FSH) and luteinizing hormone (LH). PPP2R2A is a serine-threonine phosphatase that regulates reproductive functions in both females and males, its function in pituitary cells remain unclear. Hu sheep is a highly prolific breed, which makes it suitable for studying reproductive mechanisms. In this study, the relative abundances of PPP2R2A mRNA expression were higher in the pituitary of high-prolificacy (HF) Hu sheep compared to those of low-prolificacy (LF) Hu sheep. Additionally, we demonstrated that PPP2R2A promotes pituitary cell proliferation and gonadotropin secretion using the EdU assay and ELISA, respectively. Moreover, it inhibits pituitary cell apoptosis using flow cytometry. Furthermore, PPP2R2A may affect pituitary cell function by regulating the AKT/mTOR signaling pathway. In summary, our findings suggest that PPP2R2A may play a role in regulating pituitary function and influencing the secretion of gonadotropins.
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Affiliation(s)
- Hui Xu
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Yu Cai
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Hua Yang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Shanglai Li
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Peiyong Chen
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Zongyou Wei
- Taicang Animal husbandry and veterinary station, Taicang 215400, China
| | - Feng Wang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China
| | - Ziyu Wang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
| | - Yanli Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing 210095, China.
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Lamontagne F, Paz-Trejo C, Zamorano Cuervo N, Grandvaux N. Redox signaling in cell fate: Beyond damage. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119722. [PMID: 38615720 DOI: 10.1016/j.bbamcr.2024.119722] [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: 12/18/2023] [Revised: 02/20/2024] [Accepted: 04/02/2024] [Indexed: 04/16/2024]
Abstract
This review explores the nuanced role of reactive oxygen species (ROS) in cell fate, challenging the traditional view that equates ROS with cellular damage. Through significant technological advancements in detecting localized redox states and identifying oxidized cysteines, a paradigm shift has emerged: from ROS as merely damaging agents to crucial players in redox signaling. We delve into the intricacies of redox mechanisms, which, although confined, exert profound influences on cellular physiological responses. Our analysis extends to both the positive and negative impacts of these mechanisms on cell death processes, including uncontrolled and programmed pathways. By unraveling these complex interactions, we argue against the oversimplified notion of a 'stress response', advocating for a more nuanced understanding of redox signaling. This review underscores the importance of localized redox states in determining cell fate, highlighting the sophistication and subtlety of ROS functions beyond mere damage.
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Affiliation(s)
- Felix Lamontagne
- CRCHUM - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint Denis, Montréal H2X 0A9, Québec, Canada
| | - Cynthia Paz-Trejo
- CRCHUM - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint Denis, Montréal H2X 0A9, Québec, Canada; Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal H3C 3J7, Québec, Canada
| | - Natalia Zamorano Cuervo
- CRCHUM - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint Denis, Montréal H2X 0A9, Québec, Canada
| | - Nathalie Grandvaux
- CRCHUM - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, 900 rue Saint Denis, Montréal H2X 0A9, Québec, Canada; Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal H3C 3J7, Québec, Canada.
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10
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Wu HM, Huang YY, Xu YQ, Xiang WL, Yang C, Liu RY, Li D, Guo XF, Zhang ZB, Bei CH, Tan SK, Zhu XN. Comprehensive analysis of the protein phosphatase 2A regulatory subunit B56ε in pan-cancer and its role and mechanism in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:475-492. [PMID: 38425404 PMCID: PMC10900161 DOI: 10.4251/wjgo.v16.i2.475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/10/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear. AIM To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC. METHODS The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells. RESULTS In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all P < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all P < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all P < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells. CONCLUSION B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.
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Affiliation(s)
- Hong-Mei Wu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Yuan-Yuan Huang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Yu-Qiu Xu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Wei-Lai Xiang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Chang Yang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Ru-Yuan Liu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Di Li
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Xue-Feng Guo
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Zheng-Bao Zhang
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Chun-Hua Bei
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Sheng-Kui Tan
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Nian Zhu
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China
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11
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Wang K, Chen H, Chen X, Fang Z, Xiao E, Liao Q. The Role MicroRNA-135a in Suppressing Tumor Growth in Kidney Cancer Through the Regulation of Phosphoprotein Phosphatase2A and the Activation of the AKT and ERK1/2 Signaling Pathways. J Cancer 2024; 15:999-1008. [PMID: 38230208 PMCID: PMC10788712 DOI: 10.7150/jca.90756] [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: 10/04/2023] [Accepted: 12/11/2023] [Indexed: 01/18/2024] Open
Abstract
Background: Kidney cancer is a frequently occurring malignant tumor in the urinary system, with rising morbidity and mortality rates in recent times. Developing new biomarkers and therapeutic targets is essential to improve the prognosis of patients affected by kidney cancer. In recent years, miRNAs' role in tumorigenesis and development has received growing attention. miRNAs constitute a group of small non-coding RNA molecules that regulate gene expression, affecting various biological processes, including cell proliferation, differentiation, and apoptosis. Of the many miRNAs, miR-135a plays a pivotal role in several cancers. Nevertheless, the precise mechanisms and functions concerning miR-135a in renal cancer remain incompletely understood. Therefore, this study aims to analyze the effects of miR-135a on renal cancer replication and migration and its possible mechanisms, and to provide new strategies for the diagnosis and treatment of renal cancer. Methods: Renal cell lines (ACHN, A498) with stable hyperexpression of miR-135a and reduced expression of miR-135a were constructed by lentivirus packaging. The changes of replication, clone formation and migration ability of overexpressed miR-135a and overexpressed miR-135a in ACHN and A498 renal cell lines were detected. The possible mechanism of miR-135a affecting the replication of kidney cancer was analyzed by target gene prediction, double luciferase test, Western blotting and subcutaneous tumorigenicity assay in nude mice. Results: Hyperexpression of miR-135a can inhibit kidney cancer replication, whereas miR-135a knockdown potentially enhances replication. However, neither hyperexpression nor knockdown of miR-135a affects the migration ability of kidney cancer cells. The protein expression of PP2A-B56-γ, PP2A-Cα and PP2A-Cβ in renal cell line decreased after hyperexpression of miR-135a, while the protein expression of PP2A-B56-γ, PP2A-Cα and PP2A-Cβ increased after knockdown of miR-135a. In addition, the protein expression of p-Akt and p-ERK1/2 proteins in kidney cancer cells after hyperexpression of miR-135a were down-regulated, while the protein expression of p-Akt and p-ERK1/2 were up-regulated in kidney cancer cells after knockdown of miR-135a. In subcutaneous tumor formation experiments in nude mice, tumor size within nude mice in the miR-135a group was significantly smaller than in the control group. Conclusion: MiR-135a could suppress the replication of kidney cancer by modulating PP2A and AKT, ERK1/2 signaling pathways.
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Affiliation(s)
- Kangning Wang
- Department of Urology Surgery, Xiangya Hospital Central South University, Changsha Hunan Province, 410008, China
- Department of Urology laboratory, Guangdong Medical University, Zhanjiang, Guangdong Province, 524001, China
| | - Hege Chen
- Department of Urology laboratory, Guangdong Medical University, Zhanjiang, Guangdong Province, 524001, China
| | - Xiang Chen
- Department of Urology Surgery, Xiangya Hospital Central South University, Changsha Hunan Province, 410008, China
| | - Zesong Fang
- Department of Urology laboratory, Guangdong Medical University, Zhanjiang, Guangdong Province, 524001, China
| | - Enhua Xiao
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Qiuling Liao
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
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12
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Palma FR, Gantner BN, Sakiyama MJ, Kayzuka C, Shukla S, Lacchini R, Cunniff B, Bonini MG. ROS production by mitochondria: function or dysfunction? Oncogene 2024; 43:295-303. [PMID: 38081963 DOI: 10.1038/s41388-023-02907-z] [Citation(s) in RCA: 129] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/01/2023] [Accepted: 11/21/2023] [Indexed: 01/31/2024]
Abstract
In eukaryotic cells, ATP generation is generally viewed as the primary function of mitochondria under normoxic conditions. Reactive oxygen species (ROS), in contrast, are regarded as the by-products of respiration, and are widely associated with dysfunction and disease. Important signaling functions have been demonstrated for mitochondrial ROS in recent years. Still, their chemical reactivity and capacity to elicit oxidative damage have reinforced the idea that ROS are the products of dysfunctional mitochondria that accumulate during disease. Several studies support a different model, however, by showing that: (1) limited oxygen availability results in mitochondria prioritizing ROS production over ATP, (2) ROS is an essential adaptive mitochondrial signal triggered by various important stressors, and (3) while mitochondria-independent ATP production can be easily engaged by most cells, there is no known replacement for ROS-driven redox signaling. Based on these observations and other evidence reviewed here, we highlight the role of ROS production as a major mitochondrial function involved in cellular adaptation and stress resistance. As such, we propose a rekindled view of ROS production as a primary mitochondrial function as essential to life as ATP production itself.
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Affiliation(s)
- Flavio R Palma
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Northwestern University, Chicago, IL, USA
| | - Benjamin N Gantner
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Marcelo J Sakiyama
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Northwestern University, Chicago, IL, USA
| | - Cezar Kayzuka
- Department of Pharmacology, Ribeirao Preto College of Nursing, University of Sao Paulo, Sao Paulo, Brazil
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, India
| | - Riccardo Lacchini
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Sao Paulo, Brazil
| | - Brian Cunniff
- Department of Pathology and Laboratory Medicine, Larner School of Medicine, University of Vermont, Burlington, VT, USA
| | - Marcelo G Bonini
- Department of Medicine, Division of Hematology Oncology, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Northwestern University, Chicago, IL, USA.
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13
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Labbadia J. Potential roles for mitochondria-to-HSF1 signaling in health and disease. Front Mol Biosci 2023; 10:1332658. [PMID: 38164224 PMCID: PMC10757924 DOI: 10.3389/fmolb.2023.1332658] [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: 11/03/2023] [Accepted: 12/07/2023] [Indexed: 01/03/2024] Open
Abstract
The ability to respond rapidly and efficiently to protein misfolding is crucial for development, reproduction and long-term health. Cells respond to imbalances in cytosolic/nuclear protein homeostasis through the Heat Shock Response, a tightly regulated transcriptional program that enhances protein homeostasis capacity by increasing levels of protein quality control factors. The Heat Shock Response is driven by Heat Shock Factor 1, which is rapidly activated by the appearance of misfolded proteins and drives the expression of genes encoding molecular chaperones and protein degradation factors, thereby restoring proteome integrity. HSF1 is critical for organismal health, and this has largely been attributed to the preservation of cytosolic and nuclear protein homeostasis. However, evidence is now emerging that HSF1 is also a key mediator of mitochondrial function, raising the possibility that many of the health benefits conferred by HSF1 may be due to the maintenance of mitochondrial homeostasis. In this review, I will discuss our current understanding of the interplay between HSF1 and mitochondria and consider how mitochondria-to-HSF1 signaling may influence health and disease susceptibility.
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Affiliation(s)
- Johnathan Labbadia
- Department of Genetics, Evolution and Environment, Division of Biosciences, Institute of Healthy Ageing, University College London, London, United Kingdom
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14
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Zhang Z, Tong B, Liu J, Feng J, Song L, Wang H, Ke M, Xu C, Xu Y. PP2Ac knockdown attenuates lipotoxicity‑induced pancreatic β‑cell dysfunction and apoptosis. Exp Ther Med 2023; 26:549. [PMID: 37928506 PMCID: PMC10623214 DOI: 10.3892/etm.2023.12247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 09/20/2023] [Indexed: 11/07/2023] Open
Abstract
Protein phosphatase 2A (PP2A) is one of the most common serine/threonine phosphatases in mammalian cells, and it primarily functions to regulate cell signaling, glycolipid metabolism and apoptosis. The catalytic subunit of PP2A (PP2Ac) plays an important role in the functions of the protein. However, there are few reports on the regulatory role of PP2Ac in pancreatic β-cells under lipotoxic conditions. In the present study, mouse insulinoma 6 (MIN6) pancreatic cells were transfected with short hairpin RNAs to generate PP2Ac knockdown cells and incubated with palmitate (PA) to establish a lipotoxicity model. Serine/threonine phosphatase assay system, Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay and western blotting were used to measure PP2A activity, cell viability, apoptosis, oxidative stress and insulin secretion in the cells. In addition, a mouse model of lipotoxicity was established with a high-fat diet (HFD) and the knockdown of PP2Ac using adeno-associated viruses to interfere with PP2Ac expression in the pancreatic tissues. The activity of PP2A in the mouse pancreatic tissue and the serum insulin level were measured. Furthermore, the proliferation of mouse pancreatic β-cells was assessed using pancreatic tissue immunofluorescence. PP2Ac knockdown inhibited lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic β-cells to lipotoxicity and attenuated PA-induced apoptosis in MIN6 cells. It also protected the endoplasmic reticulum and mitochondria, and ameliorated insulin secretion. The results of mRNA sequencing and western blotting analysis suggested that the protective effects of PP2Ac knockdown in MIN6 cells may be mediated via the MAPK pathway. Moreover, the results of the animal experiments suggested that specific knockdown of pancreatic PP2Ac effectively attenuated HFD-induced insulin resistance and reduced the compensatory proliferation of pancreatic β-cells in mice. In summary, the present study revealed the effects of interfering with PP2Ac gene expression on pancreatic β-cells in vivo and in vitro and the underlying mechanisms, which may provide insights for the treatment of type 2 diabetes mellitus in the clinic.
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Affiliation(s)
- Zhengwei Zhang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Beier Tong
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jie Liu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Jieyuan Feng
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Linyang Song
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Huawei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Mengting Ke
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Chengkai Xu
- Department of Endocrinology, Suizhou Central Hospital, Suizhou, Hubei 441300, P.R. China
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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15
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Guffens L, Derua R, Janssens V. PME-1 sensitizes glioblastoma cells to oxidative stress-induced cell death by attenuating PP2A-B55α-mediated inactivation of MAPKAPK2-RIPK1 signaling. Cell Death Discov 2023; 9:265. [PMID: 37500619 PMCID: PMC10374899 DOI: 10.1038/s41420-023-01572-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/13/2023] [Accepted: 07/20/2023] [Indexed: 07/29/2023] Open
Abstract
Glioblastoma (GBM) is the most common primary brain tumor in adults. Current standard therapy is surgery followed by radiotherapy, with concurrent and adjuvant temozolomide chemotherapy. GBM is characterized by almost uniformly fatal outcomes, highlighting the unmet clinical need for more efficient, biomarker-guided treatments. Protein phosphatase methylesterase-1 (PME-1), a regulator of the tumor suppressive phosphatase PP2A, promotes PP2A demethylation and inactivation, and is overexpressed in 44% of GBM, associated with increased tumor grade and cellular proliferation. Here, we aimed to investigate how reactive oxygen species (ROS), a frequent by-product of radiotherapy and temozolomide chemotherapy, regulate PP2A function via its methylesterase PME-1, and how PME-1 overexpression impacts the response of GBM cells to oxidative stress. We found that in two glioblastoma cell lines, U87MG and U251MG, expression of PME-1 is positively correlated with the sensitivity of the cells to H2O2 or t-BHP-induced oxidative stress. Experiments using the irreversible pharmacologic PME-1 inhibitor, AMZ30, and different PME-1 mutants, revealed that the methylesterase function, the PP2A binding capacity, and the nuclear localization of PME-1 are all important for the sensitizing effect of PME-1 expression. Furthermore, we identified increased nuclear localization of the PP2A-B55α subunit, increased binding of PP2A-B55α to PME-1, and increased B55α-bound PP2A-C demethylation upon oxidative stress. Lastly, we uncovered increased stress-induced phosphorylation and activity of MAPKAPK2 and RIPK1 in PME-1 overexpressing U87MG cells, which caused the observed sensitization to t-BHP treatment. Our data reveal a novel role for PME-1 in oxidative stress-induced GBM cell death, regulating nuclear PP2A-B55α activity and MAPKAPK2-RIPK1 signaling. Patients with GBM tumors overexpressing PME-1, although having a worse prognosis due to increased cellular proliferation of the tumor, could actually be more responsive to oxidative stress-inducing therapies.
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Affiliation(s)
- Liesbeth Guffens
- Laboratory of Protein Phosphorylation & Proteomics, Dept. Cellular & Molecular Medicine, KU Leuven, B-3000, Leuven, Belgium
- KU Leuven Cancer Institute (LKI), B-3000, Leuven, Belgium
| | - Rita Derua
- Laboratory of Protein Phosphorylation & Proteomics, Dept. Cellular & Molecular Medicine, KU Leuven, B-3000, Leuven, Belgium
- SyBioMa, KU Leuven, B-3000, Leuven, Belgium
| | - Veerle Janssens
- Laboratory of Protein Phosphorylation & Proteomics, Dept. Cellular & Molecular Medicine, KU Leuven, B-3000, Leuven, Belgium.
- KU Leuven Cancer Institute (LKI), B-3000, Leuven, Belgium.
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16
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Vertyshev AY, Akberdin IR, Kolpakov FA. Numerous Trigger-like Interactions of Kinases/Protein Phosphatases in Human Skeletal Muscles Can Underlie Transient Processes in Activation of Signaling Pathways during Exercise. Int J Mol Sci 2023; 24:11223. [PMID: 37446402 DOI: 10.3390/ijms241311223] [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: 01/27/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023] Open
Abstract
Optimizing physical training regimens to increase muscle aerobic capacity requires an understanding of the internal processes that occur during exercise that initiate subsequent adaptation. During exercise, muscle cells undergo a series of metabolic events that trigger downstream signaling pathways and induce the expression of many genes in working muscle fibers. There are a number of studies that show the dependence of changes in the activity of AMP-activated protein kinase (AMPK), one of the mediators of cellular signaling pathways, on the duration and intensity of single exercises. The activity of various AMPK isoforms can change in different directions, increasing for some isoforms and decreasing for others, depending on the intensity and duration of the load. This review summarizes research data on changes in the activity of AMPK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and other components of the signaling pathways in skeletal muscles during exercise. Based on these data, we hypothesize that the observed changes in AMPK activity may be largely related to metabolic and signaling transients rather than exercise intensity per se. Probably, the main events associated with these transients occur at the beginning of the exercise in a time window of about 1-10 min. We hypothesize that these transients may be partly due to putative trigger-like kinase/protein phosphatase interactions regulated by feedback loops. In addition, numerous dynamically changing factors, such as [Ca2+], metabolite concentration, and reactive oxygen and nitrogen species (RONS), can shift the switching thresholds and change the states of these triggers, thereby affecting the activity of kinases (in particular, AMPK and CaMKII) and phosphatases. The review considers the putative molecular mechanisms underlying trigger-like interactions. The proposed hypothesis allows for a reinterpretation of the experimental data available in the literature as well as the generation of ideas to optimize future training regimens.
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Affiliation(s)
| | - Ilya R Akberdin
- Department of Computational Biology, Scientific Center for Information Technologies and Artificial Intelligence, Sirius University of Science and Technology, 354340 Sochi, Russia
- Biosoft.Ru, Ltd., 630058 Novosibirsk, Russia
- Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Fedor A Kolpakov
- Department of Computational Biology, Scientific Center for Information Technologies and Artificial Intelligence, Sirius University of Science and Technology, 354340 Sochi, Russia
- Biosoft.Ru, Ltd., 630058 Novosibirsk, Russia
- Federal Research Center for Information and Computational Technologies, 630090 Novosibirsk, Russia
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17
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Lathakumari S, Seenipandian S, Balakrishnan S, Raj APMS, Sugiyama H, Namasivayam GP, Sivasubramaniam S. Identification of genes responsible for the social skill in the earthworm, Eudrilus eugeniae. GENE REPORTS 2023. [DOI: 10.1016/j.genrep.2023.101774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
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18
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Zhang W, Wang S, Jiang B, Guo M. MoRts1, a regulatory subunit of PP2A, is required for fungal development and pathogenicity of Magnaporthe oryzae. Microbiol Res 2023; 269:127313. [PMID: 36696866 DOI: 10.1016/j.micres.2023.127313] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023]
Abstract
Protein phosphatase 2 A (PP2A) is a major heterotrimeric serine/threonine protein phosphatase comprised of three subunits, including structural subunits (A), regulatory subunits (B), and catalytic subunits (C). PP2A has been widely shown to involve in a series of cell signal transduction processes such as cell metabolism, cell cycle regulation, DNA replication, gene transcription and protein translation in yeast and mammalian. However, the roles of PP2A in pathogenic fungi Magnaporthe oryzae still remain unclear. We here found that MoRts1, a gene encoding B regulatory subunit of PP2A homologous to Saccharomyces cerevisiae Rts1, showed up-regulated transcription during conidia and initially infectious stage. Subcellular localization revealed that MoRts1-eGFP was localized to the cytoplasm and septum. Targeted disruption of MoRts1 leads to a reduction of mycelial growth and sporulation, as well as the defects of hydrophobicity, melanin pigmentation and cell wall integrity (CWI). The MoRts1 mutants were less pathogenic to the host plants, compared to the Ku80 strain, and the transcriptional levels of several pathogenicity-related Rho GTPase genes, including MoCdc42, MoRho2, MoRho3, MoRho4, MoRhoX and MoRac1, were significantly decreased in the MoRts1 mutants. Besides, two splicing variants of MoRts1 with unique functions of regulating the growth and pathogenicity were identified, and the B56 domain is vital for determining the sporulation and pathogenicity of M. oryzae. Furthermore, MoRts1 was identified to interact with PP2A catalytic subunit MoPPG1 in vivo in M. oryzae. In summary, our results showed that MoRts1 is an important regulator contributing to the fungal development, and pathogenicity of M. oryzae.
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Affiliation(s)
- Weiwei Zhang
- Key Laboratory of Biology and Sustainable Management of Plant Diseases and Pests of Anhui Higher Education Institutes, Hefei 230036, China; College of Plant Protection, Anhui Agricultural University, Hefei 230036, China
| | - Shuaishuai Wang
- Key Laboratory of Biology and Sustainable Management of Plant Diseases and Pests of Anhui Higher Education Institutes, Hefei 230036, China; College of Plant Protection, Anhui Agricultural University, Hefei 230036, China
| | - Bingxin Jiang
- Key Laboratory of Biology and Sustainable Management of Plant Diseases and Pests of Anhui Higher Education Institutes, Hefei 230036, China; College of Plant Protection, Anhui Agricultural University, Hefei 230036, China
| | - Min Guo
- Key Laboratory of Biology and Sustainable Management of Plant Diseases and Pests of Anhui Higher Education Institutes, Hefei 230036, China; College of Plant Protection, Anhui Agricultural University, Hefei 230036, China.
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19
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Perrelli A, Ferraris C, Berni E, Glading AJ, Retta SF. KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease. Antioxid Redox Signal 2023; 38:496-528. [PMID: 36047808 PMCID: PMC10039281 DOI: 10.1089/ars.2021.0263] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 08/15/2022] [Accepted: 08/22/2022] [Indexed: 12/18/2022]
Abstract
Significance: KRIT1 (Krev interaction trapped 1) is a scaffolding protein that plays a critical role in vascular morphogenesis and homeostasis. Its loss-of-function has been unequivocally associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease of genetic origin characterized by defective endothelial cell-cell adhesion and ensuing structural alterations and hyperpermeability in brain capillaries. KRIT1 contributes to the maintenance of endothelial barrier function by stabilizing the integrity of adherens junctions and inhibiting the formation of actin stress fibers. Recent Advances: Among the multiple regulatory mechanisms proposed so far, significant evidence accumulated over the past decade has clearly shown that the role of KRIT1 in the stability of endothelial barriers, including the blood-brain barrier, is largely based on its involvement in the complex machinery governing cellular redox homeostasis and responses to oxidative stress and inflammation. KRIT1 loss-of-function has, indeed, been demonstrated to cause an impairment of major redox-sensitive mechanisms involved in spatiotemporal regulation of cell adhesion and signaling, which ultimately leads to decreased cell-cell junction stability and enhanced sensitivity to oxidative stress and inflammation. Critical Issues: This review explores the redox mechanisms that influence endothelial cell adhesion and barrier function, focusing on the role of KRIT1 in such mechanisms. We propose that this supports a novel model wherein redox signaling forms the common link between the various pathogenetic mechanisms and therapeutic approaches hitherto associated with CCM disease. Future Directions: A comprehensive characterization of the role of KRIT1 in redox control of endothelial barrier physiology and defense against oxy-inflammatory insults will provide valuable insights into the development of precision medicine strategies. Antioxid. Redox Signal. 38, 496-528.
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Affiliation(s)
- Andrea Perrelli
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA
| | - Chiara Ferraris
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Elisa Berni
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Angela J. Glading
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA
| | - Saverio Francesco Retta
- Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
- CCM Italia Research Network, National Coordination Center at the Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
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20
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Sharifi HJ, Paine DN, Fazzari VA, Tipple AF, Patterson E, de Noronha CMC. Sulforaphane Reduces SAMHD1 Phosphorylation To Protect Macrophages from HIV-1 Infection. J Virol 2022; 96:e0118722. [PMID: 36377871 PMCID: PMC9749475 DOI: 10.1128/jvi.01187-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
The cellular protein SAMHD1 is important for DNA repair, suppressing LINE elements, controlling deoxynucleoside triphosphate (dNTP) concentrations, maintaining HIV-1 latency, and preventing excessive type I interferon responses. SAMHD1 is also a potent inhibitor of HIV-1 and other significant viral pathogens. Infection restriction is due in part to the deoxynucleoside triphosphatase (dNTPase) activity of SAMHD1 but is also mediated through a dNTPase-independent mechanism that has been described but not explored. The phosphorylation of SAMHD1 at threonine 592 (T592) controls many of its functions. Retroviral restriction, irrespective of dNTPase activity, is linked to unphosphorylated T592. Sulforaphane (SFN), an isothiocyanate, protects macrophages from HIV infection by mobilizing the transcription factor and antioxidant response regulator Nrf2. Here, we show that SFN and other clinically relevant Nrf2 mobilizers reduce SAMHD1 T592 phosphorylation to protect macrophages from HIV-1. We further show that SFN, through Nrf2, triggers the upregulation of the cell cycle control protein p21 in human monocyte-derived macrophages to contribute to SAMHD1 activation. We additionally present data that support another, potentially redox-dependent mechanism employed by SFN to contribute to SAMHD1 activation through reduced phosphorylation. This work establishes the use of exogenous Nrf2 mobilizers as a novel way to study virus restriction by SAMHD1 and highlights the Nrf2 pathway as a potential target for the therapeutic control of SAMHD1 cellular and antiviral functions. IMPORTANCE Here, we show, for the first time, that the treatment of macrophages with Nrf2 mobilizers, known activators of antioxidant responses, increases the fraction of SAMHD1 without a regulatory phosphate at position 592. We demonstrate that this decreases infection of macrophages by HIV-1. Phosphorylated SAMHD1 is important for DNA repair, the suppression of LINE elements, the maintenance of HIV-1 in a latent state, and the prevention of excessive type I interferon responses, while unphosphorylated SAMHD1 blocks HIV infection. SAMHD1 impacts many viruses and is involved in various cancers, so knowledge of how it works and how it is regulated has broad implications for the development of therapeutics. Redox-modulating therapeutics are already in clinical use or under investigation for the treatment of many conditions. Thus, understanding the impact of redox modifiers on controlling SAMHD1 phosphorylation is important for many areas of research in microbiology and beyond.
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Affiliation(s)
- H. John Sharifi
- Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | - Dakota N. Paine
- Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | | | | | - Emilee Patterson
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA
| | - Carlos M. C. de Noronha
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA
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21
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Elsayed S, Elsaid KA. Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model. Front Pharmacol 2022; 13:1033520. [PMID: 36467056 PMCID: PMC9712728 DOI: 10.3389/fphar.2022.1033520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/07/2022] [Indexed: 08/08/2023] Open
Abstract
Background: Gout is a common arthritis, due to deposition of monosodium urate (MSU) crystals which results in IL-1β secretion by tissue-resident macrophages. Xanthine oxidase (XO) catalyzes uric acid (UA) production and in the process, reactive oxygen species (ROS) are generated which contributes to NLRP3 inflammasome activation. Protein phosphatase 2A (PP2A) may be involved in regulating inflammatory pathways in macrophages. The objective of this study was to investigate whether PP2A regulates gout inflammation, mediated by XO activity modulation. We studied UA and ROS generations in MSU stimulated murine bone marrow derived macrophages (BMDMs) in response to fingolimod phosphate, a PP2A activator, and compared its anti-inflammatory efficacy to that of an XO inhibitor, febuxostat. Methods: BMDMs were stimulated with MSU, GM-CSF/IL-1β or nigericin ± fingolimod (2.5 μM) or febuxostat (200 μM) and UA levels, ROS, XO, and PP2A activities, Xdh (XO) expression and secreted IL-1β levels were determined. PP2A activity and IL-1β in MSU stimulated BMDMs ± N-acetylcysteine (NAC) (10 μM) ± okadaic acid (a PP2A inhibitor) were also determined. M1 polarization of BMDMs in response to MSU ± fingolimod treatment was assessed by a combination of iNOS expression and multiplex cytokine assay. The in vivo efficacy of fingolimod was assessed in a murine peritoneal model of acute gout where peritoneal lavages were studied for pro-inflammatory classical monocytes (CMs), anti-inflammatory nonclassical monocytes (NCMs) and neutrophils by flow cytometry and IL-1β by ELISA. Results: Fingolimod reduced intracellular and secreted UA levels (p < 0.05), Xdh expression (p < 0.001), XO activity (p < 0.001), ROS generation (p < 0.0001) and IL-1β secretion (p < 0.0001), whereas febuxostat enhanced PP2A activity (p < 0.05). NAC treatment enhanced PP2A activity and reduced XO activity and PP2A restoration mediated NAC's efficacy as co-treatment with okadaic acid increased IL-1β secretion (p < 0.05). Nigericin activated caspase-1 and reduced PP2A activity (p < 0.001) and fingolimod reduced caspase-1 activity in BMDMs (p < 0.001). Fingolimod reduced iNOS expression (p < 0.0001) and secretion of IL-6 and TNF-α (p < 0.05). Fingolimod reduced CMs (p < 0.0001), neutrophil (p < 0.001) and IL-1β (p < 0.05) lavage levels while increasing NCMs (p < 0.001). Conclusion: Macrophage PP2A is inactivated in acute gout by ROS and a PP2A activator exhibited a broad anti-inflammatory effect in acute gout in vitro and in vivo.
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22
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Hwang S, Ha Y, Koo G, Noh H, Lee A, Kim B, Hong SM, Morgan MJ, Eyun S, Lee D, Roe J, Lee Y, Kim Y. LCK-Mediated RIPK3 Activation Controls Double-Positive Thymocyte Proliferation and Restrains Thymic Lymphoma by Regulating the PP2A-ERK Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2204522. [PMID: 36161785 PMCID: PMC9661840 DOI: 10.1002/advs.202204522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/07/2022] [Indexed: 06/16/2023]
Abstract
Receptor-interacting protein kinase 3 (RIPK3) is the primary regulator of necroptotic cell death. RIPK3 expression is often silenced in various cancer cells, which suggests that it may have tumor suppressor properties. However, the exact mechanism by which RIPK3 negatively regulates cancer development and progression remains unclear. This report indicates that RIPK3 acts as a potent regulator of the homeostatic proliferation of CD4+ CD8+ double-positive (DP) thymocytes. Abnormal proliferation of RIPK3-deficient DP thymocytes occurs independently of the well-known role for RIPK3 in necroptosis (upstream of MLKL activation), and is associated with an incidental thymic mass, likely thymic hyperplasia. In addition, Ripk3-null mice develop increased thymic tumor formation accompanied by reduced host survival in the context of an N-ethyl-N-nitrosourea (ENU)-induced tumor model. Moreover, RIPK3 deficiency in p53-null mice promotes thymic lymphoma development via upregulated extracellular signal-regulated kinase (ERK) signaling, which correlates with markedly reduced survival rates. Mechanistically, lymphocyte-specific protein tyrosine kinase (LCK) activates RIPK3, which in turn leads to increases in the phosphatase activity of protein phosphatase 2 (PP2A), thereby suppressing hyper-activation of ERK in DP thymocytes. Overall, these findings suggest that a RIPK3-PP2A-ERK signaling axis regulates DP thymocyte homeostasis and may provide a potential therapeutic target to improve thymic lymphoma therapies.
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Affiliation(s)
- Sung‐Min Hwang
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Sandra and Edward Meyer Cancer Center and Department of Obstetrics and GynecologyWeill Cornell MedicineNew YorkNY10065USA
| | - Yu‐Jin Ha
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Gi‐Bang Koo
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Hyun‐Jin Noh
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - A‐Yeon Lee
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Byeong‐Ju Kim
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Sun Mi Hong
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Michael J. Morgan
- Department of Natural SciencesNortheastern State UniversityTahlequahOK74464USA
| | - Seong‐il Eyun
- Department of Life ScienceChung‐Ang UniversitySeoul06973Republic of Korea
| | - Dakeun Lee
- Department of PathologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - Jae‐Seok Roe
- Department of BiochemistryCollege of Life Science and BiotechnologyYonsei UniversitySeoul03722Republic of Korea
| | - Youngsoo Lee
- Institute of Medical ScienceAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
| | - You‐Sun Kim
- Department of Biochemistry and Molecular BiologyAjou University School of Medicine164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
- Department of Biomedical SciencesGraduate School of Ajou University164 Worldcup‐ro, Yeongtong‐gu, SuwonGyeonggi‐do16499Republic of Korea
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23
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Demir S, Wolff G, Wieder A, Maida A, Bühler L, Brune M, Hautzinger O, Feuchtinger A, Poth T, Szendroedi J, Herzig S, Ekim Üstünel B. TSC22D4 interacts with Akt1 to regulate glucose metabolism. SCIENCE ADVANCES 2022; 8:eabo5555. [PMID: 36269831 PMCID: PMC9586482 DOI: 10.1126/sciadv.abo5555] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 08/31/2022] [Indexed: 06/13/2023]
Abstract
Maladaptive insulin signaling is a key feature in the pathogenesis of severe metabolic disorders, including obesity and diabetes. Enhancing insulin sensitivity represents a major goal in the treatment of patients affected by diabetes. Here, we identify transforming growth factor-β1 stimulated clone 22 D4 (TSC22D4) as a novel interaction partner for protein kinase B/Akt1, a critical mediator of insulin/phosphatidylinositol 3-kinase signaling pathway. While energy deprivation and oxidative stress promote the TSC22D4-Akt1 interaction, refeeding mice or exposing cells to glucose and insulin impairs this interaction, which relies on an intrinsically disordered region (D2 domain) within TSC22D4. Functionally, the interaction with TSC22D4 reduces basal phosphorylation of Akt and its downstream targets during starvation, thereby promoting insulin sensitivity. Genetic, liver-specific reconstitution experiments in mice demonstrate that the interaction between TSC22D4 and Akt1 improves glucose handling and insulin sensitivity. Overall, our findings postulate a model whereby TSC22D4 acts as an environmental sensor and interacts with Akt1 to regulate insulin signaling and glucose metabolism.
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Affiliation(s)
- Sevgican Demir
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Gretchen Wolff
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Annika Wieder
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Adriano Maida
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Lea Bühler
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Maik Brune
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Oksana Hautzinger
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Annette Feuchtinger
- Research Unit Analytical Pathology, German Research Center for Environmental Health, Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
| | - Tanja Poth
- Center for Model System and Comparative Pathology (CMCP), Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Julia Szendroedi
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Stephan Herzig
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Bilgen Ekim Üstünel
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Center, Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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24
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Wang B, Tan Y, Zhou W, Yang J, Jiang Y, Liu X, Zhan Z. Loss of BTK ameliorates the pathological cardiac fibrosis and dysfunction. Matrix Biol 2022; 112:171-189. [PMID: 36031013 DOI: 10.1016/j.matbio.2022.08.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/30/2022] [Accepted: 08/24/2022] [Indexed: 01/14/2023]
Abstract
Cardiac fibrosis is a common irreversible pathological feature of diverse heart disorders. Uncontrolled cardiac fibrosis contributes to maladaptive cardiac remodeling and eventually heart failure. However, the molecular determinants of ischemic and non-ischemic pathological cardiac fibrosis remain largely unknown. Here, we investigated the role of Bruton's tyrosine kinase (BTK) in cardiac fibrosis and remodeling of mice under various pathological conditions. BTK expression was increased in myocardium of mice after pressure overload or myocardial infarction (MI). BTK was mainly located in cardiac fibroblasts of myocardium, and its expression in isolated cardiac fibroblasts was also upregulated following TGF-β treatment. The deficiency or pharmacological inhibition of BTK with the second-generation inhibitor Acalabrutinib attenuated cardiac fibrosis, preserved cardiac function and prevented adverse cardiac remodeling, which protected against heart failure in mice following pressure overload or MI. BTK deficiency or inhibitor treatment significantly decreased the expression of pro-fibrotic molecules in isolated cardiac fibroblasts and inhibited the transition of fibroblasts to myofibroblasts in response to diverse pathological stresses. BTK directly bound and phosphorylated TGF-β receptor Ⅰ (TβRⅠ) at tyrosine 182, and then promoted the activation of downstream SMAD-dependent or -independent TGF-β signaling, leading to the enhanced transition of fibroblasts to pro-fibrotic myofibroblasts and the excessive extracellular matrix gene expression. Our finding uncovers a driving role of BTK in cardiac fibrosis and dysfunction following pressure overload and MI stress, and highlights novel pathogenic mechanisms in ischemic and non-ischemic maladaptive cardiac remodeling, which presents as a promising target for the development of anti-fibrotic therapy.
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Affiliation(s)
- Bo Wang
- Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yong Tan
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Wenhui Zhou
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Jing Yang
- Department of Cardiology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui hospital, Fudan University, Shanghai 200031, China
| | - Yuyu Jiang
- Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China
| | - Xingguang Liu
- Department of Pathogen Biology, Naval Medical University, Shanghai 200433, China.
| | - Zhenzhen Zhan
- Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
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25
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Guo CL. Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis. Front Cell Dev Biol 2022; 10:862791. [PMID: 35774228 PMCID: PMC9237464 DOI: 10.3389/fcell.2022.862791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/29/2022] [Indexed: 12/19/2022] Open
Abstract
Organ development, homeostasis, and repair often rely on bidirectional, self-organized cell-niche interactions, through which cells select cell fate, such as stem cell self-renewal and differentiation. The niche contains multiplexed chemical and mechanical factors. How cells interpret niche structural information such as the 3D topology of organs and integrate with multiplexed mechano-chemical signals is an open and active research field. Among all the niche factors, reactive oxygen species (ROS) have recently gained growing interest. Once considered harmful, ROS are now recognized as an important niche factor in the regulation of tissue mechanics and topology through, for example, the HIF-YAP-Notch signaling pathways. These pathways are not only involved in the regulation of stem cell physiology but also associated with inflammation, neurological disorder, aging, tumorigenesis, and the regulation of the immune checkpoint molecule PD-L1. Positive feedback circuits have been identified in the interplay of ROS and HIF-YAP-Notch signaling, leading to the possibility that under aberrant conditions, self-organized, ROS-dependent physiological regulations can be switched to self-perpetuating dysregulation, making ROS a double-edged sword at the interface of stem cell physiology and tumorigenesis. In this review, we discuss the recent findings on how ROS and tissue mechanics affect YAP-HIF-Notch-PD-L1 signaling, hoping that the knowledge can be used to design strategies for stem cell-based and ROS-targeting therapy and tissue engineering.
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Affiliation(s)
- Chin-Lin Guo
- Institute of Physics, Academia Sinica, Taipei, Taiwan
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26
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Tuncay A, Noble A, Guille M, Cobley JN. RedoxiFluor: A microplate technique to quantify target-specific protein thiol redox state in relative percentage and molar terms. Free Radic Biol Med 2022; 181:118-129. [PMID: 35131446 PMCID: PMC8904371 DOI: 10.1016/j.freeradbiomed.2022.01.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/12/2022] [Accepted: 01/23/2022] [Indexed: 12/12/2022]
Abstract
Unravelling how reactive oxygen species regulate fundamental biological processes is hampered by the lack of an accessible microplate technique to quantify target-specific protein thiol redox state in percentages and moles. To meet this unmet need, we present RedoxiFluor. RedoxiFluor uses two spectrally distinct thiol-reactive fluorescent conjugated reporters, a capture antibody, detector antibody and a standard curve to quantify target-specific protein thiol redox state in relative percentage and molar terms. RedoxiFluor can operate in global mode to assess the redox state of the bulk thiol proteome and can simultaneously assess the redox state of multiple targets in array mode. Extensive proof-of-principle experiments robustly validate the assay principle and the value of each RedoxiFluor mode in diverse biological contexts. In particular, array mode RedoxiFluor shows that the response of redox-regulated phosphatases to lipopolysaccharide (LPS) differs in human monocytes. Specifically, LPS increased PP2A-, SHP1-, PTP1B-, and CD45-specific reversible thiol oxidation without changing the redox state of calcineurin, PTEN, and SHP2. The relative percentage and molar terms are interpretationally useful and define the most complete and extensive microplate redox analysis achieved to date. RedoxiFluor is a new antibody technology with the power to quantify relative target-specific protein thiol redox state in percentages and moles relative to the bulk thiol proteome and selected other targets in a widely accessible, simple and easily implementable microplate format.
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Affiliation(s)
- Ahmet Tuncay
- Redox Biology Group, UHI, Inverness, IV2 3JH, UK
| | - Anna Noble
- European Xenopus Resource Centre, University of Portsmouth, Portsmouth, PO1 2DY, UK
| | - Matthew Guille
- European Xenopus Resource Centre, University of Portsmouth, Portsmouth, PO1 2DY, UK
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27
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Muggeridge DJ, Crabtree DR, Tuncay A, Megson IL, Davison G, Cobley JN. Exercise decreases PP2A-specific reversible thiol oxidation in human erythrocytes: Implications for redox biomarkers. Free Radic Biol Med 2022; 182:73-78. [PMID: 35217176 DOI: 10.1016/j.freeradbiomed.2022.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/07/2022] [Accepted: 02/18/2022] [Indexed: 10/19/2022]
Abstract
New readily accessible systemic redox biomarkers are needed to understand the biological roles reactive oxygen species (ROS) play in humans because overtly flawed, technically fraught, and unspecific assays severely hamper translational progress. The antibody-linked oxi-state assay (ALISA) makes it possible to develop valid ROS-sensitive target-specific protein thiol redox state biomarkers in a readily accessible microplate format. Here, we used a maximal exercise bout to disrupt redox homeostasis in a physiologically meaningful way to determine whether the catalytic core of the serine/threonine protein phosphatase PP2A is a candidate systemic redox biomarker in human erythrocytes. We reasoned that: constitutive oxidative stress (e.g., haemoglobin autoxidation) would sensitise erythrocytes to disrupted ion homeostasis as manifested by increased oxidation of the ion regulatory phosphatase PP2A. Unexpectedly, an acute bout of maximal exercise lasting ~16 min decreased PP2A-specific reversible thiol oxidation (redox ratio, rest: 0.46; exercise: 0.33) without changing PP2A content (rest: 193 pg/ml; exercise: 191 pg/ml). The need for only 3-4 μl of sample to perform ALISA means PP2A-specific reversible thiol oxidation is a capillary-fingertip blood-compatible candidate redox biomarker. Consistent with biologically meaningful redox regulation, thiol reductant-inducible PP2A activity was significantly greater (+10%) at rest compared to exercise. We establish a route to developing new readily measurable protein thiol redox biomarkers for understanding the biological roles ROS play in humans.
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Affiliation(s)
- David J Muggeridge
- Division of Biomedical Sciences, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH, Scotland, UK; Edinburgh Napier University, Edinburgh, Scotland, UK
| | - Daniel R Crabtree
- Division of Biomedical Sciences, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH, Scotland, UK
| | - Ahmet Tuncay
- Division of Biomedical Sciences, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH, Scotland, UK
| | - Ian L Megson
- Division of Biomedical Sciences, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH, Scotland, UK
| | - Gareth Davison
- Sport and Exercise Research Institute, Ulster University, Newtownabbey, Northern Ireland, UK
| | - James N Cobley
- Division of Biomedical Sciences, University of the Highlands and Islands, Old Perth Road, Inverness, IV2 3JH, Scotland, UK.
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28
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ElSayed S, Jay GD, Cabezas R, Qadri M, Schmidt TA, Elsaid KA. Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs. Front Immunol 2022; 12:771677. [PMID: 34992596 PMCID: PMC8725049 DOI: 10.3389/fimmu.2021.771677] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022] Open
Abstract
Objectives To compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes. Methods Acute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed. Results Enhanced phagocytic activation of gout monocytes under basal conditions (p<0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p<0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p<0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p<0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p<0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p<0.05). Conclusions MSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.
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Affiliation(s)
- Sandy ElSayed
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, United States
| | - Gregory D Jay
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
| | - Ralph Cabezas
- Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
| | - Marwa Qadri
- Department of Pharmacology, School of Pharmacy, Jazan University, Jazan, Saudi Arabia
| | - Tannin A Schmidt
- Biomedical Engineering Department, University of Connecticut Health Center, Farmington, CT, United States
| | - Khaled A Elsaid
- Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, United States
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29
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Ozel B, Kipcak S, Biray Avci C, Gunduz C, Saydam G, Aktan C, Selvi Gunel N. Combination of dasatinib and okadaic acid induces apoptosis and cell cycle arrest by targeting protein phosphatase PP2A in chronic myeloid leukemia cells. Med Oncol 2022; 39:46. [PMID: 35092492 DOI: 10.1007/s12032-021-01643-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 12/28/2021] [Indexed: 11/28/2022]
Abstract
Chronic myeloid leukemia (CML) is a cancer type of the white blood cells and because of BCR-ABL translocation it results in increased tyrosine kinase activity. For this purpose, dasatinib is the second-generation tyrosine kinase inhibitor that is used for inhibition of BCR-ABL. Effectively and safetly, dasatinib has been used for imatinib-intolerant/resistant CML patients. Protein phosphatase 2A (PP2A) is the major serine/threonine phosphatase ensuring cellular homeostasis in cells and is associated with many cancer types including leukemias. In this study, we aimed to investigate the effects of dasatinib and okadaic acid (OA), either alone or in combination, on apoptosis and cell cycle arrest and dasatinib effect on enzyme activity and protein-level changes of PP2A in K562 cell line. The cytotoxic effects of dasatinib were evaluated by WST-1 analysis. Apoptosis was determined by Annexin V and Apo-Direct assays by flow cytometry. Cell cycle arrest analysis was performed for the investigation of the cytostatic effect. We also used OA as a PP2A inhibitor to assess apoptosis and cell cycle arrest changes in case of reducing the level of PP2A. PP2A enyzme activity and protein levels of PP2A were examined by serine/threonine phosphatase assay and Western blot analysis, respectively. Apoptosis was increased with dasatinib and OA combination. Cell cycle arrest was determined especially after OA treatment. The enzyme activity was decreased depending on time after dasatinib application. PP2A regulatory and catalytic subunit protein levels were decreased compared to control. Targeting the PP2A by dasatinib and OA has potential for CML treatment.
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Affiliation(s)
- Buket Ozel
- Medical Biology Department, Faculty of Medicine, Ege University, Izmir, Turkey.
| | - Sezgi Kipcak
- Medical Biology Department, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Cigir Biray Avci
- Medical Biology Department, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Cumhur Gunduz
- Medical Biology Department, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Guray Saydam
- Division of Haematology, Department of Internal Medicine, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Cagdas Aktan
- Medical Biology Department, Faculty of Medicine, Beykent University, Istanbul, Turkey
| | - Nur Selvi Gunel
- Medical Biology Department, Faculty of Medicine, Ege University, Izmir, Turkey
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Liang J, Huang Y, Yang C, Huang S, Xie J, Nong X, Liu J, Zhang Y, Zhang Z. The effect of PPP2CA expression on the prognosis of patients with hepatocellular carcinoma and its molecular biological characteristics. J Gastrointest Oncol 2021; 12:3008-3021. [PMID: 35070426 PMCID: PMC8748071 DOI: 10.21037/jgo-21-720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/06/2021] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND To investigate the role of the PPP2CA gene in the prognosis of patients with hepatocellular carcinoma (HCC) and its molecular biological characteristics. METHODS We performed comparison of the expression of PPP2CA in HCC and non-HCC tissues of HCC patients who underwent surgery for the first time in the Tumor Hospital of Guangxi Medical University from July 2017 to July 2019, and retrospectively analyzed the relevant clinical data and prognosis. The GSE76427 data set and bioinformatics and public databases were used to compare the expression of PPP2CA between HCC and non-cancer tissues. Gene Ontology (GO) analysis was performed of PPP2CA and its differential genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. A protein-protein interaction (PPI) network of PPP2CA and its differentially expressed genes (DEGs) was constructed from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and visualized by Cytoscape software. RESULTS The immunohistochemistry (IHC) of tissue sections confirmed that PPP2CA was highly expressed in most HCC tissues; the high expression of PPP2CA was significantly correlated with microvascular invasion (MVI) and portal vein tumor thrombi (P<0.05). Participants in the PPP2CA high expression group had worse overall survival (OS; P=0.04) and recurrence-free survival (RFS; P=0.019). The PPP2CA gene and 71 DEGs were mainly enriched in the nuclear division, organelle fission, nuclear chromosome separation, and chromatid separation process, and KEGG analysis revealed enrichment in drug metabolism-cytochrome metabolism of xenobiotics by P450 and cytochrome P450. Finally, through the PPI network, CCNA2, AURKB, TOP2A, NCAPG, MCM2, CDC20, CCMB2, AURKA, and MGST1 were identified as the top 9 highly connected hub genes. CONCLUSIONS The PPP2CA gene is highly expressed in HCC tissues. The high expression of PPP2CA is significantly associated with poor prognosis. Through the analysis of DEGs, GO and KEGG pathway analysis, it was found that PPP2CA may act on liver cancer through multiple targets and multiple pathways, and PPP2CA plays a promoting role in HCC.
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Affiliation(s)
- Jingchang Liang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu Huang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Chenglei Yang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shen Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jinlong Xie
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xiang Nong
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jianyong Liu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yumei Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhiming Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
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Regulation of Cardiac PKA Signaling by cAMP and Oxidants. Antioxidants (Basel) 2021; 10:antiox10050663. [PMID: 33923287 PMCID: PMC8146537 DOI: 10.3390/antiox10050663] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 12/31/2022] Open
Abstract
Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.
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Batinic-Haberle I, Tovmasyan A, Huang Z, Duan W, Du L, Siamakpour-Reihani S, Cao Z, Sheng H, Spasojevic I, Alvarez Secord A. H 2O 2-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6653790. [PMID: 33815656 PMCID: PMC7987459 DOI: 10.1155/2021/6653790] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Mn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3 •-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.
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Affiliation(s)
- Ines Batinic-Haberle
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Artak Tovmasyan
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Zhiqing Huang
- Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Weina Duan
- Departments of Anesthesiology, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Li Du
- Departments of Anesthesiology, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | | | - Zhipeng Cao
- Departments of Anesthesiology, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Huaxin Sheng
- Departments of Anesthesiology, Neurobiology, and Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ivan Spasojevic
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Pharmacokinetics/Pharmacodynamics (PK/PD) Core Laboratory, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Angeles Alvarez Secord
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
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Fojtík P, Beckerová D, Holomková K, Šenfluk M, Rotrekl V. Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells. Front Cell Dev Biol 2021; 8:607444. [PMID: 33553145 PMCID: PMC7859355 DOI: 10.3389/fcell.2020.607444] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
Mild hypoxia (5% O2) as well as FGFR1-induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and MAPK signaling pathways markedly support pluripotency in human pluripotent stem cells (hPSCs). This study demonstrates that the pluripotency-promoting PI3K/AKT signaling pathway is surprisingly attenuated in mild hypoxia compared to the 21% O2 environment. Hypoxia is known to be associated with lower levels of reactive oxygen species (ROS), which are recognized as intracellular second messengers capable of upregulating the PI3K/AKT signaling pathway. Our data denote that ROS downregulation results in pluripotency upregulation and PI3K/AKT attenuation in a hypoxia-inducible factor 1 (HIF-1)-dependent manner in hPSCs. Using specific MAPK inhibitors, we show that the MAPK pathway also downregulates ROS and therefore attenuates the PI3K/AKT signaling—this represents a novel interaction between these signaling pathways. This inhibition of ROS initiated by MEK1/2–ERK1/2 may serve as a negative feedback loop from the MAPK pathway toward FGFR1 and PI3K/AKT activation. We further describe the molecular mechanism resulting in PI3K/AKT upregulation in hPSCs—ROS inhibit the PI3K's primary antagonist PTEN and upregulate FGFR1 phosphorylation. These novel regulatory circuits utilizing ROS as second messengers may contribute to the development of enhanced cultivation and differentiation protocols for hPSCs. Since the PI3K/AKT pathway often undergoes an oncogenic transformation, our data could also provide new insights into the regulation of cancer stem cell signaling.
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Affiliation(s)
- Petr Fojtík
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czechia
| | - Deborah Beckerová
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czechia
| | - Katerina Holomková
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Martin Šenfluk
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czechia
| | - Vladimir Rotrekl
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, Czechia
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Williams R, Laskovs M, Williams RI, Mahadevan A, Labbadia J. A Mitochondrial Stress-Specific Form of HSF1 Protects against Age-Related Proteostasis Collapse. Dev Cell 2020; 54:758-772.e5. [DOI: 10.1016/j.devcel.2020.06.038] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 05/11/2020] [Accepted: 06/29/2020] [Indexed: 12/21/2022]
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Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 2020; 20:74-88. [PMID: 31686003 PMCID: PMC7314312 DOI: 10.1038/s41568-019-0216-7] [Citation(s) in RCA: 1282] [Impact Index Per Article: 256.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/30/2019] [Indexed: 02/06/2023]
Abstract
The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
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Affiliation(s)
- Gerta Hoxhaj
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Brendan D Manning
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
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Xu J, Lu Y, Liu Q, Xia A, Zhao J, Xu X, Sun Q, Qi F, Sun B. Long noncoding RNA GMAN promotes hepatocellular carcinoma progression by interacting with eIF4B. Cancer Lett 2019; 473:1-12. [PMID: 31875526 DOI: 10.1016/j.canlet.2019.12.032] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/06/2019] [Accepted: 12/18/2019] [Indexed: 12/24/2022]
Abstract
Gastric cancer metastasis associated long noncoding RNA (GMAN), a long noncoding RNA, is associated with metastasis in gastric cancer. However, its underlying mechanisms in hepatocellular carcinoma (HCC) are unclear. We found that lncRNA-GMAN was significantly overexpressed in HCC tissues. GMAN expression is associated with vascular invasion, histological grade, tumor, node, metastasis (TNM) stage, short overall survival, and disease-free survival. Knockdown of GMAN induced apoptosis and suppressed invasive and migration potential in vitro and vivo, whereas ectopic GMAN expression produced the opposite effect. We also found that the inhibition of apoptosis, rather than promotion of proliferation, was responsible for GMAN-enhanced cellular viability. Mechanistic analyses indicated that GMAN directly combined with eukaryotic translation initiation factor 4B (eIF4B) and promoted its phosphorylation at serine-422 by preventing eIF4B binding and dephosphorization of the protein phosphatase 2A subunit B. The results demonstrated the stability of p-eIF4B and the elevation of mRNA translation and anti-apoptosis-related protein expression, which further induced proliferation and metastasis of HCC. The current study demonstrates that GMAN regulates the progression of HCC by inhibiting apoptosis and promoting the survival of cancer cells.
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Affiliation(s)
- Jianbo Xu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China; Department of Hepatobiliary Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 223001, Huai'an No.1, Jiangsu Province, PR China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Yijun Lu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Qiaoyu Liu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Anliang Xia
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
| | - Jian Zhao
- Department of Hepatobiliary Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 223001, Huai'an No.1, Jiangsu Province, PR China.
| | - Xiaoliang Xu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China.
| | - Qikai Sun
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China.
| | - Fuzhen Qi
- Department of Hepatobiliary Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, 223001, Huai'an No.1, Jiangsu Province, PR China.
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 210000, Nanjing, Jiangsu Province, PR China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
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Clark AR, Ohlmeyer M. Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration. Pharmacol Ther 2019; 201:181-201. [PMID: 31158394 PMCID: PMC6700395 DOI: 10.1016/j.pharmthera.2019.05.016] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 05/29/2019] [Indexed: 12/11/2022]
Abstract
Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric enzyme that catalyzes the selective removal of phosphate groups from protein serine and threonine residues. Emerging evidence suggests that it functions as a tumor suppressor by constraining phosphorylation-dependent signalling pathways that regulate cellular transformation and metastasis. Therefore, PP2A-activating drugs (PADs) are being actively sought and investigated as potential novel anti-cancer treatments. Here we explore the concept that PP2A also constrains inflammatory responses through its inhibitory effects on various signalling pathways, suggesting that PADs may be effective in the treatment of inflammation-mediated pathologies.
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Affiliation(s)
- Andrew R Clark
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
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