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Wang Y, Su X, Wang Q, Zhang L, Yu Y, Zhao Y, Liu Z. Bisphenol A exposure enhances proliferation and tumorigenesis of papillary thyroid carcinoma through ROS generation and activation of NOX4 signaling pathways. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 292:117946. [PMID: 40014988 DOI: 10.1016/j.ecoenv.2025.117946] [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: 11/22/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/01/2025]
Abstract
As a prevalent industrial material and component of consumer products, bisphenol A (BPA) is linked to hormone homeostasis disruption and potential carcinogenicity. However, the precise mechanisms through which BPA contributes to thyroid carcinogenesis, especially in papillary thyroid carcinoma (PTC), are not fully understood. This study investigates how BPA boosts the proliferation and tumorigenic characteristics of thyroid cells. BPA exposure significantly increased cell proliferation in a duration-dependent manner at a concentration of 0.5 μM, which is slightly higher than human exposure levels. Therefore, this study utilized BPA treatment concentrations of 0.1 µM and 0.5 µM. BPA augmented the invasiveness of PTC cells with a dependency on both dosage and temporal factors. RNA-seq and gene expression analysis from normal human thyroid follicular epithelial cells suggested that BPA upregulated genes related to oxidative stress and thyroid cancer. Concurrently, our study revealed significant upregulation of NOX4 in thyroid tumors compared to normal thyroid tissues, with higher expression levels observed in advanced carcinomas by analyses of the TCGA database. BPA induces the upregulation of NOX4 in human thyroid cells, thereby triggering the activation of MAPK and PI3K/AKT pathways. In xenograft models, BPA treatment resulted in increased tumor size and Ki-67 proliferation index, accompanied by upregulated NOX4 expression. Additionally, BPA exposure led to higher levels of free triiodothyronine (FT3), indicating thyroid hormone disruption. Mechanistically, BPA activates the MAPK and PI3K/AKT pathways via NOX4, leading to increased ROS production and cell proliferation. This was further demonstrated through the use of ROS scavenger treatment and si-NOX4, which showed that BPA stimulates ROS generation by activating NOX4/MAPK and NOX4/PI3K/AKT pathways in thyroid cells. This finding enhances our understanding of the pathogenesis of PTC related to BPA exposure and highlights the necessity for rigorous health risk assessments regarding BPA exposure.
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Affiliation(s)
- Yi Wang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xuling Su
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Qianqian Wang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Likun Zhang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yaling Yu
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yiwei Zhao
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zhiyan Liu
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Hervieu M, Legrand AJ, Floquet E, Idziorek T, Spriet C, Monté D, Villeret V, Aumercier M, Choul‐li S. PARP-1 Inhibition Increases Oxidative Stress in Ets-1-Expressing MDA-MB-231 Breast Cancer Cells. Cancer Rep (Hoboken) 2025; 8:e70119. [PMID: 39778077 PMCID: PMC11706972 DOI: 10.1002/cnr2.70119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 12/02/2024] [Accepted: 12/29/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND The Ets-1 transcription factor plays a primordial role in regulating the expression of numerous genes implicated in cancer progression. In a previous study, we revealed that poly(ADP-ribose) polymerase-1 (PARP-1) inhibition by PJ-34 results in Ets-1 level increase in cells, which is related with cell death of Ets-1-expressing cancer cells. AIMS The mechanism of the antitumor effect of PARP-1 inhibition was investigated in the Ets-1-expressing MDA-MB-231 breast cancer cells. METHODS AND RESULTS We tested the effects of four PARP inhibitors (PARPi) (PJ-34, Veliparib, Olaparib, and Rucaparib). We first demonstrated that PARPi reduced cells growth through G2/M cell cycle arrest. Next, we evaluated PARP-1 inhibition effect on oxidative DNA damage in Ets-1-overexpressing and Ets-1-non-expressing breast cancer cells and we showed that PARPi led only Ets-1-overexpressing cells to accumulate it, which triggers the DNA damage response as revealed by the increase in the level of a panel of DNA damage-related proteins. Importantly, we demonstrated that PARPi increased reactive oxygen species (ROS), only in Ets-1-overexpressing cells and this is accompanied by upregulation of p47phox expression, a subunit of the NAPDH oxidase (NOX). CONCLUSION These preliminary findings correlate PARPi-induced oxidative DNA damage/oxidative stress to Ets-1 expression in breast cancer cells.
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Affiliation(s)
- Magalie Hervieu
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Arnaud J. Legrand
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Emilie Floquet
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Thierry Idziorek
- Univ. Lille, CNRS, Inserm, CHU LilleUMR9020‐U1277‐CANTHER‐Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | - Corentin Spriet
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US41‐UMS2014‐PLBS, F‐59000, Lille, France; Univ. Lille, CNRSUMR8576‐UGSF‐Structural and Functional Glycobiology UnitLilleFrance
| | - Didier Monté
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Vincent Villeret
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Marc Aumercier
- CNRS EMR9002 Integrative Structural BiologyLilleFrance
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de LilleU1167‐RID‐AGE‐Risk Factors and Molecular Determinants of Aging‐Related DiseasesLilleFrance
| | - Souhaila Choul‐li
- Département de Biologie, Faculté des SciencesUniversité Chouaïb DoukkaliEl JadidaMorocco
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3
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Petrachkova T, Soldatkina O, Leduy L, Nepveu A. The BCL11A transcription factor stimulates the enzymatic activities of the OGG1 DNA glycosylase. Biol Chem 2024; 405:711-726. [PMID: 39272221 PMCID: PMC11712033 DOI: 10.1515/hsz-2024-0088] [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: 06/10/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024]
Abstract
The BCL11A transcription factor has previously been shown to interact with and stimulate the enzymatic activities of the NTHL1 DNA glycosylase and Pol β polymerase. Here we show that BCL11A and a smaller peptide encompassing amino acids 160 to 520 can interact with the 8-oxoguanine DNA glycosylase, OGG1, increase the binding of OGG1 to DNA that contains an 8-oxoguanine base and stimulate the glycosylase activity of OGG1. Following BCL11A knockdown, we observed an increase in oxidized purines in the genome using comet assays, while immunoassays reveal an increase in 8-oxoG bases. Structure-function analysis indicates that the stimulation of OGG1 by BCL11A requires the zinc fingers 1, 2 and 3 as well as the proline-rich region between the first and second zing finger, but a glutamate-rich region downstream of zinc finger 3 is dispensable. Ectopic expression of a small peptide that contains the three zinc fingers can rescue the increase in 8-oxoguanine caused by BCL11A knockdown. These findings, together with previous results showing that BCL11A stimulates the enzymatic activities of NTHL1 and the Pol β polymerase, suggest that high expression of BCL11A is important to protect cancer cells against oxidative DNA damage.
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Affiliation(s)
- Tetiana Petrachkova
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Olha Soldatkina
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Lam Leduy
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Alain Nepveu
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Medicine, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Oncology, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
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Maurizio A, Tascini AS, Morelli MJ. SurfR: Riding the wave of RNA-seq data with a comprehensive bioconductor package to identify surface protein-coding genes. BIOINFORMATICS ADVANCES 2024; 5:vbae201. [PMID: 39735574 PMCID: PMC11671034 DOI: 10.1093/bioadv/vbae201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 11/26/2024] [Accepted: 12/12/2024] [Indexed: 12/31/2024]
Abstract
Motivation Proteins at the cell surface connect signaling networks and largely determine a cell's capacity to communicate and interact with its environment. In particular, variations in transcriptomic profiles are often observed between healthy and diseased cells, leading to distinct sets of cell-surface proteins. For these reasons, cell-surface proteins may act as biomarkers for the detection of cells of interest in tissues or body fluids, are often the target of pharmaceutical agents, and hold significant promise in the clinical practice for diagnosis, prognosis, treatment development, and evaluation of therapy response. Therefore, implementing robust methods to identify condition-specific cell-surface proteins is of pivotal importance to advance biomedical research. Results We developed SurfR, an R/Bioconductor package providing a streamlined end-to-end workflow for computationally identifying surface protein-coding genes from expression data. Our user-friendly, comprehensive workflow performs systematic expression data retrieval from public databases, differential gene expression across conditions, integration of datasets, enrichment analysis, identification of targetable proteins on a condition of interest, and data visualization. Availability and implementation SurfR is released under GNU-GPL-v3.0 License. Source code, documentation, examples, and tutorials are available through Bioconductor (http://www.bioconductor.org/packages/SurfR). RMD notebooks with the use cases code described in the manuscript can be found on GitHub (https://github.com/auroramaurizio/SurfR_UseCases).
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Affiliation(s)
- Aurora Maurizio
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Anna Sofia Tascini
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Universita‘Vita-Salute San Raffaele, Milan 20132, Italy
| | - Marco J Morelli
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
- Universita‘Vita-Salute San Raffaele, Milan 20132, Italy
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5
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Grootaert MOJ. Cell senescence in cardiometabolic diseases. NPJ AGING 2024; 10:46. [PMID: 39433786 PMCID: PMC11493982 DOI: 10.1038/s41514-024-00170-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/05/2024] [Indexed: 10/23/2024]
Abstract
Cellular senescence has been implicated in many age-related pathologies including atherosclerosis, heart failure, age-related cardiac remodeling, diabetic cardiomyopathy and the metabolic syndrome. Here, we will review the characteristics of senescent cells and their endogenous regulators, and summarize the metabolic stressors that induce cell senescence. We will discuss the evidence of cell senescence in the onset and progression of several cardiometabolic diseases and the therapeutic potential of anti-senescence therapies.
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Affiliation(s)
- Mandy O J Grootaert
- Endocrinology, Diabetes and Nutrition, UCLouvain, Brussels, Belgium.
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
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Igarashi T, Yano K, Endo S, Shiotani B. Tolerance of Oncogene-Induced Replication Stress: A Fuel for Genomic Instability. Cancers (Basel) 2024; 16:3507. [PMID: 39456601 PMCID: PMC11506635 DOI: 10.3390/cancers16203507] [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: 09/12/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Activation of oncogenes disturbs a wide variety of cellular processes and induces physiological dysregulation of DNA replication, widely referred to as replication stress (RS). Oncogene-induced RS can cause replication forks to stall or collapse, thereby leading to DNA damage. While the DNA damage response (DDR) can provoke an anti-tumor barrier to prevent the development of cancer, a small subset of cells triggers replication stress tolerance (RST), allowing precancerous cells to survive, thereby promoting clonal expansion and genomic instability (GIN). Genomic instability (GIN) is a hallmark of cancer, driving genetic alterations ranging from nucleotide changes to aneuploidy. These alterations increase the probability of oncogenic events and create a heterogeneous cell population with an enhanced ability to evolve. This review explores how major oncogenes such as RAS, cyclin E, and MYC induce RS through diverse mechanisms. Additionally, we delve into the strategies employed by normal and cancer cells to tolerate RS and promote GIN. Understanding the intricate relationship between oncogene activation, RS, and GIN is crucial to better understand how cancer cells emerge and to develop potential cancer therapies that target these vulnerabilities.
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Affiliation(s)
- Taichi Igarashi
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; (T.I.); (K.Y.); (S.E.)
- Department of Biosciences, School of Science, Kitasato University, Minami-ku, Sagamihara-city, Kanagawa 252-0373, Japan
| | - Kimiyoshi Yano
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; (T.I.); (K.Y.); (S.E.)
| | - Syoju Endo
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; (T.I.); (K.Y.); (S.E.)
- Department of NCC Cancer Science, Division of Integrative Molecular Biomedicine, Biomedical Sciences and Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Bunsyo Shiotani
- Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; (T.I.); (K.Y.); (S.E.)
- Department of Genome Stress Signaling, Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan
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7
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Gorini F, Tonacci A. Vitamin C in the Management of Thyroid Cancer: A Highway to New Treatment? Antioxidants (Basel) 2024; 13:1242. [PMID: 39456495 PMCID: PMC11505632 DOI: 10.3390/antiox13101242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/10/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy, with an increased global incidence in recent decades, despite a substantially unchanged survival. While TC has an excellent overall prognosis, some types of TC are associated with worse patient outcomes, depending on the genetic setting. Furthermore, oxidative stress is related to more aggressive features of TC. Vitamin C, an essential nutrient provided with food or as a dietary supplement, is a well-known antioxidant and a scavenger of reactive oxygen species; however, at high doses, it can induce pro-oxidant effects, acting through multiple biological mechanisms that play a crucial role in killing cancer cells. Although experimental data and, less consistently, clinical studies, suggest the possibility of antineoplastic effects of vitamin C at pharmacological doses, the antitumor efficacy of this nutrient in TC remains at least partly unexplored. Therefore, this review discusses the current state of knowledge on the role of vitamin C, alone or in combination with other conventional therapies, in the management of TC, the mechanisms underlying this association, and the perspectives that may emerge in TC treatment strategies, and, also, in light of the development of novel functional foods useful to this extent, by implementing novel sensory analysis strategies.
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Affiliation(s)
- Francesca Gorini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy;
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8
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Stoyanov M, Martinikova AS, Matejkova K, Horackova K, Zemankova P, Burdova K, Zemanova Z, Kleiblova P, Kleibl Z, Macurek L. PPM1D activity promotes cellular transformation by preventing senescence and cell death. Oncogene 2024; 43:3081-3093. [PMID: 39237765 PMCID: PMC11473410 DOI: 10.1038/s41388-024-03149-3] [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: 05/02/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 09/07/2024]
Abstract
Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active RAS oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.
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Affiliation(s)
- Miroslav Stoyanov
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Andra S Martinikova
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Katerina Matejkova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Klara Horackova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Zemankova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Kamila Burdova
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Zemanova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Kleiblova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Zdenek Kleibl
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Libor Macurek
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
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9
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Huber T, Horioka-Duplix M, Chen Y, Saca VR, Ceraudo E, Chen Y, Sakmar TP. The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence. Sci Signal 2024; 17:eadp3967. [PMID: 39288219 PMCID: PMC11920964 DOI: 10.1126/scisignal.adp3967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024]
Abstract
In contrast with sun exposure-induced melanoma, rarer melanocytic tumors and neoplasms with low mutational burden present opportunities to study isolated signaling mechanisms. These include uveal melanoma and blue nevi, which are often driven by mutations within the G protein-coupled signaling cascade downstream of cysteinyl leukotriene receptor 2. Here, we review how the same mutations within this pathway drive the growth of melanocytes in one tissue but can inhibit the growth of those in another, exemplifying the role of the tissue environment in the delicate balance between uncontrolled cell growth and senescence.
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Affiliation(s)
- Thomas Huber
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
| | - Mizuho Horioka-Duplix
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Yuanhuang Chen
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Victoria R Saca
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Emilie Ceraudo
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
| | - Yu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas P Sakmar
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
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10
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Ma L, Yu J, Fu Y, He X, Ge S, Jia R, Zhuang A, Yang Z, Fan X. The dual role of cellular senescence in human tumor progression and therapy. MedComm (Beijing) 2024; 5:e695. [PMID: 39161800 PMCID: PMC11331035 DOI: 10.1002/mco2.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 08/21/2024] Open
Abstract
Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence-associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.
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Affiliation(s)
- Liang Ma
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Jie Yu
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Yidian Fu
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Xiaoyu He
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Shengfang Ge
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Renbing Jia
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Ai Zhuang
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Zhi Yang
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
| | - Xianqun Fan
- Department of OphthalmologyNinth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghaiChina
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11
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Wang Y, Ge H, Chen P, Wang Y. Wnt/β-catenin signaling in corneal epithelium development, homeostasis, and pathobiology. Exp Eye Res 2024; 246:110022. [PMID: 39117134 DOI: 10.1016/j.exer.2024.110022] [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: 04/18/2024] [Revised: 07/07/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
The corneal epithelium is located on the most anterior surface of the eyeball and protects against external stimuli. The development of the corneal epithelium and the maintenance of corneal homeostasis are essential for the maintenance of visual acuity. It has been discovered recently via the in-depth investigation of ocular surface illnesses that the Wnt/β-catenin signaling pathway is necessary for the growth and stratification of corneal epithelial cells as well as the control of endothelial cell stability. In addition, the Wnt/β-catenin signaling pathway is directly linked to the development of common corneal illnesses such as keratoconus, fungal keratitis, and corneal neovascularization. This review mainly summarizes the role of the Wnt/β-catenin signaling pathway in the development, homeostasis, and pathobiology of cornea, hoping to provide new insights into the study of corneal epithelium and the treatment of related diseases.
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Affiliation(s)
- Yihui Wang
- School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Huanhuan Ge
- School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Peng Chen
- School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| | - Ye Wang
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao, Shandong 266042, China.
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12
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Turkoglu B, Mansuroglu B. Investigating the Effects of Chelidonic Acid on Oxidative Stress-Induced Premature Cellular Senescence in Human Skin Fibroblast Cells. Life (Basel) 2024; 14:1070. [PMID: 39337855 PMCID: PMC11433492 DOI: 10.3390/life14091070] [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: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
This study investigated the effects of chelidonic acid (CA) on hydrogen peroxide (H2O2) induced cellular senescence in human skin fibroblast cells (BJ). Cellular senescence is a critical mechanism that is linked to age-related diseases and chronic conditions. CA, a γ-pyrone compound known for its broad pharmacological activity, was assessed for its potential to mitigate oxidative stress and alter senescence markers. A stress-induced premature senescence (SIPS) model was designed in BJ fibroblast cells using the oxidative stress agent H2O2. After this treatment, cells were treated with CA, and the potential effect of CA on senescence was evaluated using senescence-related β-galactosidase, 4',6-diamino-2-phenylindole (DAPI), acridine-orange staining (AO), comet assay, molecular docking assays, gene expression, and protein analysis. These results demonstrate that CA effectively reduces senescence markers, including senescence-associated β-galactosidase activity, DNA damage, lysosomal activity, and oxidative stress indicators such as malondialdehyde. Molecular docking revealed CA's potential interactions with critical proteins involved in senescence signalling pathways, suggesting mechanisms by which CA may exert its effects. Gene expression and protein analyses corroborated the observed anti-senescent effects, with CA modulating p16, p21, and pRB1 expressions and reducing oxidative stress markers. In conclusion, CA appeared to have senolytic and senomorphic potential in vitro, which could mitigate and reverse SIPS markers in BJ fibroblasts.
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Affiliation(s)
| | - Banu Mansuroglu
- Department of Molecular Biology and Genetics, Faculty of Arts and Science, Yildiz Technical University, Istanbul 34220, Turkey;
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13
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Robert M, Kennedy BK, Crasta KC. Therapy-induced senescence through the redox lens. Redox Biol 2024; 74:103228. [PMID: 38865902 PMCID: PMC11215421 DOI: 10.1016/j.redox.2024.103228] [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: 05/08/2024] [Revised: 05/22/2024] [Accepted: 06/04/2024] [Indexed: 06/14/2024] Open
Abstract
Therapy-induced senescent tumor cells have emerged as significant drivers of tumor recurrence and disease relapse. Interestingly, reactive oxygen species (ROS) production and its associated redox signaling networks are intertwined with initiation and establishment of therapy-induced senescence. Therapy-induced senescent cells influence neighboring cells and the tumor microenvironment via their bioactive secretome known as the senescence-associated secretory phenotype (SASP). The intracellular effects of ROS are dose and context-dependent. Under normal physiological conditions, ROS is involved in various signalling pathways and cellular processes important for maintenance of cellular homeostasis, such as redox balance, stress response, inflammatory signalling, cell proliferation and cell death among others. However excess ROS accompanied by a pro-oxidant microenvironment can engender oxidative DNA damage, triggering cellular senescence. In this review, we discuss the role of ROS and the redox state dynamics in fine-tuning homeostatic processes that drive therapy-induced cell fate towards senescence establishment, as well as their influence in stimulating inflammatory signalling and SASP production. We also offer insights into interventional strategies, specifically senotherapeutics, that could potentially leverage on modulation of redox and antioxidant pathways. Lastly, we evaluate possible implications of redox rewiring during escape from therapy-induced senescence, an emerging area of research. We envision that examining therapy-induced senescence through the redox lens, integrated with time-resolved single-cell RNA sequencing combined with spatiotemporal multi-omics, could further enhance our understanding of its functional heterogeneity. This could aid identification of targetable signalling nodes to reduce disease relapse, as well as inform strategies for development of broad-spectrum senotherapeutics. Overall, our review aims to delineate redox-driven mechanisms which contribute to the biology of therapy-induced senescence and beyond, while highlighting implications for tumor initiation and recurrence.
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Affiliation(s)
- Matius Robert
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Brian K Kennedy
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Karen C Crasta
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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14
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Muro P, Zhang L, Li S, Zhao Z, Jin T, Mao F, Mao Z. The emerging role of oxidative stress in inflammatory bowel disease. Front Endocrinol (Lausanne) 2024; 15:1390351. [PMID: 39076514 PMCID: PMC11284038 DOI: 10.3389/fendo.2024.1390351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/19/2024] [Indexed: 07/31/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive system and includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stress markers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlate with the severity of the disease. Thus, oxidative stress markers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD.
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Affiliation(s)
- Peter Muro
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Zhang
- Nanjing Lishui People’s Hospital, Zhongda Hospital, Southeast University, Nanjing, China
| | - Shuxuan Li
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zihan Zhao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tao Jin
- Department of Gastrointestinal and Endoscopy, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhenwei Mao
- The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China
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15
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Lu Y, Sun J, Yang M, Xing Y, Zhu W, Zhu J, Ma X, Wang Y, Wang L, Jia Y. Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:6178-6188. [PMID: 38483540 DOI: 10.1021/acs.jafc.3c05243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Ferroptosis holds great potential as a therapeutic approach for gastric cancer (GC), a prevalent and deadly malignant tumor associated with high rates of incidence and mortality. Myricetin, well-known for its multifaceted biomedical attributes, particularly its anticancer properties, has yet to be thoroughly investigated regarding its involvement in ferroptosis. The aim of this research was to elucidate the impact of myricetin on ferroptosis in GC progression. The present study observed that myricetin could trigger ferroptosis in GC cells by enhancing malondialdehyde production and Fe2+ accumulation while suppressing glutathione levels. Mechanistically, myricetin directly interacted with NADPH oxidase 4 (NOX4), influencing its stability by inhibiting its ubiquitin degradation. Moreover, myricetin regulated the inhibition of ferroptosis induced by Helicobacter pylori cytotoxin-associated gene A (CagA) through the NOX4/NRF2/GPX4 pathway. In vivo experiments demonstrated that myricetin treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice. It was accompanied by increased NOX4 expression in tumor tissue and suppression of the NRF2/GPX4 antioxidant pathway. Therefore, this research underscores myricetin as a novel inducer of ferroptosis in GC cells through its interaction with NOX4. It is a promising candidate for GC treatment.
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Affiliation(s)
- Yi Lu
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Jingguo Sun
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Mingyue Yang
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Yuanxin Xing
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Wenshuai Zhu
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Jingyu Zhu
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
| | - Xiaoli Ma
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Yunshan Wang
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
| | - Lu Wang
- Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan 2250013, People's Republic of China
| | - Yanfei Jia
- Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, People's Republic of China
- Research Center of Basic Medicine, Jinan Central Hospital, Shandong University, Jinan 250013, People's Republic of China
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16
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Chida T, Watanabe S, Ohta K, Noritake H, Ito M, Suzuki T, Suda T, Kawata K. Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress. Free Radic Biol Med 2024; 212:199-206. [PMID: 38103659 DOI: 10.1016/j.freeradbiomed.2023.12.014] [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: 06/18/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite the accumulation of clinical data showing the impact of amino acid substitutions at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive liver diseases, including HCC, the underlying mechanisms have not been elucidated. We analyzed 72 liver biopsy specimens from patients with chronic HCV genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related factor 2 (NRF2) in the nucleus were quantified using liver tissue immunohistochemistry. The effects of amino acid substitutions in the HCV core region on hepatocellular oxidative stress were investigated using wild-type or double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in human hepatoma HuH-7 cells. Overall, 24, 19, 11, and 18 patients had the wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with the wild-type disease. Increased levels of intracellular superoxide and hydrogen peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide phosphate oxidase 4 were augmented in cells treated with R70Q+L91M. HCV core proteins harboring either or both substitutions of R70Q/H or L91M enhanced hepatocellular oxidative stress in vivo and in vitro. These amino acid substitutions may affect HCC development by enhancing hepatic oxidative stress in patients with chronic HCV-1b infection.
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Affiliation(s)
- Takeshi Chida
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan; Department of Regional Medical Care Support, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Shinya Watanabe
- Department of Gastroenterology, Shimada General Medical Center, 1200-5 Noda, Shimada, Shizuoka, 427-8502, Japan
| | - Kazuyoshi Ohta
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Masahiko Ito
- Department of Microbiology & Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Tetsuro Suzuki
- Department of Microbiology & Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Takafumi Suda
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
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17
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Mogck BA, Jezak ST, Wiley CD. Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging. Biomedicines 2024; 12:414. [PMID: 38398016 PMCID: PMC10886841 DOI: 10.3390/biomedicines12020414] [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: 12/19/2023] [Revised: 02/06/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Cellular senescence is a complex stress response marked by stable proliferative arrest and the secretion of biologically active molecules collectively known as the senescence-associated secretory phenotype (SASP). Mitochondria-derived reactive oxygen species (ROS) have been implicated in aging and age-related processes, including senescence. Stressors that increase ROS levels promote both senescence and the SASP, while reducing mitochondrial ROS or mitochondria themselves can prevent senescence or the SASP. Mitochondrially targeted catalase (mCAT), a transgene that reduces mitochondrial levels of ROS, has been shown to extend the lifespan of murine models and protect against the age-related loss of mitochondrial function. However, it remains unclear whether mCAT can prevent senescence or the SASP. In this study, we investigated the impact of mCAT on senescence in cultured cells and aged mice in order to discover if the lifespan-extending activity of mCAT might be due to the reduction in senescent cells or the SASP. Contrary to expectations, we observed that mCAT does not reduce markers of senescence or the SASP in cultured cells. Moreover, mCAT does not prevent the accumulation of senescent cells or the development of the SASP in adipose tissue from aged mice. These results suggest that mitochondrial ROS may not always play a causal role in the development of senescence during natural aging and underscore the need for a nuanced understanding of the intricate relationship between mitochondrial ROS and cellular senescence.
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Affiliation(s)
- Bronwyn A. Mogck
- Jean Mayer USDA Human Nutrition Research on Aging, Tufts University, Boston, MA 02111, USA
- SENS Research Foundation, Mountain View, CA 94041, USA
| | - Samantha T. Jezak
- Jean Mayer USDA Human Nutrition Research on Aging, Tufts University, Boston, MA 02111, USA
- Friedman School of Nutrition Science & Policy, Tufts University, Boston, MA 02111, USA
| | - Christopher D. Wiley
- Jean Mayer USDA Human Nutrition Research on Aging, Tufts University, Boston, MA 02111, USA
- Friedman School of Nutrition Science & Policy, Tufts University, Boston, MA 02111, USA
- Department of Medicine, School of Medicine, Tufts University, Boston, MA 02111, USA
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18
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Vickridge E, Faraco CCF, Lo F, Rahimian H, Liu Z, Tehrani P, Djerir B, Ramdzan ZM, Leduy L, Maréchal A, Gingras AC, Nepveu A. The function of BCL11B in base excision repair contributes to its dual role as an oncogene and a haplo-insufficient tumor suppressor gene. Nucleic Acids Res 2024; 52:223-242. [PMID: 37956270 PMCID: PMC10783527 DOI: 10.1093/nar/gkad1037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/13/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Genetic studies in mice and human cancers established BCL11B as a haploinsufficient tumor suppressor gene. Paradoxically, BCL11B is overexpressed in some human cancers where its knockdown is synthetic lethal. We identified the BCL11B protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro DNA repair assays demonstrated that both BCL11B and a small recombinant BCL11B213-560 protein lacking transcription regulation potential can stimulate the enzymatic activities of two base excision repair (BER) enzymes: NTHL1 and Pol β. In cells, BCL11B is rapidly recruited to sites of DNA damage caused by laser microirradiation. BCL11B knockdown delays, whereas ectopic expression of BCL11B213-560 accelerates, the repair of oxidative DNA damage. Inactivation of one BCL11B allele in TK6 lymphoblastoid cells causes an increase in spontaneous and radiation-induced mutation rates. In turn, ectopic expression of BCL11B213-560 cooperates with the RAS oncogene in cell transformation by reducing DNA damage and cellular senescence. These findings indicate that BCL11B functions as a BER accessory factor, safeguarding normal cells from acquiring mutations. Paradoxically, it also enables the survival of cancer cells that would otherwise undergo senescence or apoptosis due to oxidative DNA damage resulting from the elevated production of reactive oxygen species.
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Affiliation(s)
- Elise Vickridge
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Camila C F Faraco
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Fanny Lo
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Hedyeh Rahimian
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Zi Yang Liu
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Payman S Tehrani
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario Canada
| | - Billel Djerir
- Department of Biology and Cancer Research Institute, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Zubaidah M Ramdzan
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Lam Leduy
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
| | - Alexandre Maréchal
- Department of Biology and Cancer Research Institute, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Alain Nepveu
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Medicine, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
- Department of Oncology, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada
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19
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Wu Z, Qu J, Zhang W, Liu GH. Stress, epigenetics, and aging: Unraveling the intricate crosstalk. Mol Cell 2024; 84:34-54. [PMID: 37963471 DOI: 10.1016/j.molcel.2023.10.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/09/2023] [Accepted: 10/11/2023] [Indexed: 11/16/2023]
Abstract
Aging, as a complex process involving multiple cellular and molecular pathways, is known to be exacerbated by various stresses. Because responses to these stresses, such as oxidative stress and genotoxic stress, are known to interplay with the epigenome and thereby contribute to the development of age-related diseases, investigations into how such epigenetic mechanisms alter gene expression and maintenance of cellular homeostasis is an active research area. In this review, we highlight recent studies investigating the intricate relationship between stress and aging, including its underlying epigenetic basis; describe different types of stresses that originate from both internal and external stimuli; and discuss potential interventions aimed at alleviating stress and restoring epigenetic patterns to combat aging or age-related diseases. Additionally, we address the challenges currently limiting advancement in this burgeoning field.
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Affiliation(s)
- Zeming Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Jing Qu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Weiqi Zhang
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; China National Center for Bioinformation, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; The Fifth People's Hospital of Chongqing, Chongqing 400062, China.
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
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20
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Caligiuri A, Becatti M, Porro N, Borghi S, Marra F, Pastore M, Taddei N, Fiorillo C, Gentilini A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants (Basel) 2023; 13:28. [PMID: 38247453 PMCID: PMC10812651 DOI: 10.3390/antiox13010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
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Affiliation(s)
- Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Nunzia Porro
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Serena Borghi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
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21
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Ratliffe J, Kataura T, Otten EG, Korolchuk VI. The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity. Bioessays 2023; 45:e2300076. [PMID: 37603398 PMCID: PMC11475373 DOI: 10.1002/bies.202300076] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/14/2023] [Accepted: 08/02/2023] [Indexed: 08/22/2023]
Abstract
Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age-related diseases associated with impaired autophagy and oxidative stress.
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Affiliation(s)
- Joshua Ratliffe
- Biosciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Tetsushi Kataura
- Biosciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Elsje G. Otten
- Biosciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
- Present address:
Amphista TherapeuticsCambridgeUK
| | - Viktor I. Korolchuk
- Biosciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
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22
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Zhou Y, Zhang A, Fang C, Yuan L, Shao A, Xu Y, Zhou D. Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy. CNS Neurosci Ther 2023; 29:2744-2759. [PMID: 37341156 PMCID: PMC10493678 DOI: 10.1111/cns.14315] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/29/2023] [Accepted: 06/07/2023] [Indexed: 06/22/2023] Open
Abstract
Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.
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Affiliation(s)
- Yuhang Zhou
- The First Clinical Medical CollegeHeilongjiang University of Chinese MedicineHarbinChina
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
| | - Anke Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chaoyou Fang
- Department of Neurosurgery, Shanghai General Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ling Yuan
- School of Public Health, School of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yuanzhi Xu
- Department of Neurosurgery, Huashan Hospital, School of MedicineFudan UniversityShanghaiChina
| | - Danyang Zhou
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
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23
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Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023; 11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open
Abstract
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions. Therefore, they promote angiogenesis through the same neovascularization pathway used physiologically. Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress; the latter being one of the most powerful stimuli of angiogenesis. As a result of altered tumor metabolism due to hypoxia, acidosis occurs. The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers. The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers, ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies. In particular, in the treatment of patients with similar clinical tumor phenotypes but different prognoses, the new biomarkers could be useful. Moreover, they may lead to a better understanding of the mechanisms underlying drug resistance. Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells, which require a high vascular supply.
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Affiliation(s)
- Luigi Gaetano Andriolo
- Department of General and Specialistic Surgery Paride Stefanini, Policlinico Umberto I, University of Rome Sapienza, Rome 06100, Italy
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Danilo Alunni Fegatelli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Michele Chicone
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Gaetano Di Rienzo
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | | | - Giambattista Lobreglio
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Giovanni Serio
- Pathological Anatomy Unit, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
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24
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Tao Y, Chen W, Xu H, Xu J, Yang H, Luo X, Chen M, He J, Bai Y, Qi H. Adipocyte-Derived Exosomal NOX4-Mediated Oxidative Damage Induces Premature Placental Senescence in Obese Pregnancy. Int J Nanomedicine 2023; 18:4705-4726. [PMID: 37608820 PMCID: PMC10441661 DOI: 10.2147/ijn.s419081] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/11/2023] [Indexed: 08/24/2023] Open
Abstract
Background A recent study has reported that maternal obesity is linked to placental oxidative damage and premature senescence. NADPH oxidase 4 (NOX4) is massively expressed in adipose tissue, and its induced reactive oxygen species have been found to contribute to cellular senescence. While, whether, in obese pregnancy, adipose tissue-derived NOX4 is the considerable cause of placental senescence remained elusive. Methods This study collected term placentas from obese and normal pregnancies and obese pregnant mouse model was constructed by a high fat diet to explore placental senescence. Furthermore, adipocyte-derived exosomes were isolated from primary adipocyte medium of obese and normal pregnancies to examine their effect on placenta functions in vivo and vitro. Results The placenta from the obese group showed a significant increase in placental oxidative damage and senescence. Exosomes from obese adipocytes contained copies of NOX4, and when cocultured with HTR8/SVneo cells, they induced severe oxidative damage, cellular senescence, and suppressed proliferation and invasion functions when compared with the control group. In vivo, adipocyte-derived NOX4-containing exosomes could induce placental oxidative damage and senescence, ultimately leading to adverse pregnancy outcomes. Conclusion In obesity, adipose tissue can secrete exosomes containing NOX4 which can be delivered to trophoblast resulting in severe DNA oxidative damage and premature placental senescence, ultimately leading to adverse pregnancy outcomes.
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Affiliation(s)
- Yuelan Tao
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Wei Chen
- Department of Emergency & Intensive Care Units, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hongbing Xu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Jiacheng Xu
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Huan Yang
- Department of Obstetrics, Chongqing University Three Gorges Hospital, Chongqing, 404100, People’s Republic of China
| | - Xin Luo
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Miaomiao Chen
- Maternal and Child Health Hospital of Hubei Province, Wuhan City, Hubei Province, 430070, People’s Republic of China
| | - Jie He
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Yuxiang Bai
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Hongbo Qi
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Women and Children’s Hospital of Chongqing Medical University, Chongqing, 401147, People’s Republic of China
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25
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Fenniche S, Oukabli M, Oubaddou Y, Chahdi H, Damiri A, Alghuzlan A, Laraqui A, Dakka N, Bakri Y, Dupuy C, Ameziane El Hassani R. A Comparative Analysis of NOX4 Protein Expression in Malignant and Non-Malignant Thyroid Tumors. Curr Issues Mol Biol 2023; 45:5811-5823. [PMID: 37504283 PMCID: PMC10378117 DOI: 10.3390/cimb45070367] [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: 05/17/2023] [Revised: 06/08/2023] [Accepted: 06/14/2023] [Indexed: 07/29/2023] Open
Abstract
The comparative analysis of the expression of the reactive oxygen species-generating NADPH oxidase NOX4 from TCGA data shows that the NOX4 transcript is upregulated in papillary thyroid carcinomas (PTC)-BRAFV600E tumors compared to PTC-BRAFwt tumors. However, a comparative analysis of NOX4 at the protein level in malignant and non-malignant tumors is missing. We explored NOX4 protein expression by immunohistochemistry staining in malignant tumors (28 classical forms of PTC (C-PTC), 17 follicular variants of PTC (F-PTC), and three anaplastic thyroid carcinomas (ATCs)) and in non-malignant tumors (six lymphocytic thyroiditis, four Graves' disease, ten goiters, and 20 hyperplasias). We detected the BRAFV600E mutation by Sanger sequencing and digital droplet PCR. The results show that NOX4 was found to be higher (score ≥ 2) in C-PTC (92.9%) compared to F-PTC (52.9%) and ATC (33.3%) concerning malignant tumors. Interestingly, all C-PTC-BRAFV600E expressed a high score for NOX4 at the protein level, strengthening the positive correlation between the BRAFV600E mutation and NOX4 expression. In addition, independent of the mutational status of BRAF, we observed that 90% of C-PTC infiltrating tumors showed high NOX4 expression, suggesting that NOX4 may be considered a complementary biomarker in PTC aggressiveness. Interestingly, NOX4 was highly expressed in non-malignant thyroid diseases with different subcellular localizations.
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Affiliation(s)
- Salma Fenniche
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 1014, Morocco
- Gustave Roussy Cancer Campus, Pavillon de Recherche N°2, F-94805 Villejuif, France
- Faculty of Medicine and Pharmacy, University Paris-Saclay, F-91400 Orsay, France
- Unité Mixte de Recherche UMR9019 Centre National de la Recherche Scientifique, Pavillon de Recherche N°2, F-94805 Villejuif, France
| | - Mohamed Oukabli
- Service of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Rabat 1014, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Yassire Oubaddou
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 1014, Morocco
| | - Hafsa Chahdi
- Service of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Rabat 1014, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Amal Damiri
- Service of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Rabat 1014, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Abir Alghuzlan
- Gustave Roussy Cancer Campus, Pavillon de Recherche N°2, F-94805 Villejuif, France
- Unité Mixte de Recherche UMR9019 Centre National de la Recherche Scientifique, Pavillon de Recherche N°2, F-94805 Villejuif, France
| | - Abdelilah Laraqui
- Service of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Rabat 1014, Morocco
| | - Nadia Dakka
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 1014, Morocco
| | - Youssef Bakri
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 1014, Morocco
| | - Corinne Dupuy
- Gustave Roussy Cancer Campus, Pavillon de Recherche N°2, F-94805 Villejuif, France
- Faculty of Medicine and Pharmacy, University Paris-Saclay, F-91400 Orsay, France
- Unité Mixte de Recherche UMR9019 Centre National de la Recherche Scientifique, Pavillon de Recherche N°2, F-94805 Villejuif, France
| | - Rabii Ameziane El Hassani
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 1014, Morocco
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26
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Hebishy M, Shintouo CM, Dufait I, Debacq-Chainiaux F, Bautmans I, Njemini R. Heat shock proteins and cellular senescence in humans: A systematic review. Arch Gerontol Geriatr 2023; 113:105057. [PMID: 37207540 DOI: 10.1016/j.archger.2023.105057] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/27/2023] [Accepted: 05/07/2023] [Indexed: 05/21/2023]
Abstract
Cellular senescence (CS) is a permanent arrest of cell growth and exit of the cell cycle. It is an important tumor suppression mechanism and has a key role in wound healing, tissue regeneration, and prevention of tissue fibrosis. Despite the short-term benefits of CS, accumulation of senescent cells has deleterious effects and is associated with several pathological age-related phenotypes. As Heat Shock Proteins (HSP) are associated with cyto-protection, their role in longevity and CS became a research interest. However, an overview of the relationship between HSP and CS in humans still lacks in the literature. To provide an overview of the current state of the literature, this systematic review focused on the role of HSP in the development of CS in humans. PubMed, Web of Science and Embase were systematically screened for studies on the relationship between HSP and CS in humans. A total of 14 articles were eligible for inclusion. The heterogeneity and lack of numerical reporting of outcomes obstructed the conduction of a meta-analysis. The results consistently show that HSP depletion results in increased CS, while overexpression of HSP decreases CS, whether in cancer, fibroblasts, or stem cell lines. This systematic review summarized the literature on the prospective role of HSP in the development of CS in humans.
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Affiliation(s)
- Mariam Hebishy
- Department of Gerontology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium
| | - Cabirou Mounchili Shintouo
- Department of Gerontology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium; Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium; Department of Biochemistry and Molecular Biology, Faculty of Science, University of Buea, P.O. Box 63 Buea, Cameroon
| | - Ines Dufait
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, Brussels 1090, Belgium
| | - Florence Debacq-Chainiaux
- Research Unit on Cellular Biology (URBC), Department of Biology, University of Namur, Rue de Bruxelles, 61, Namur B-5000, Belgium
| | - Ivan Bautmans
- Department of Gerontology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium; Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium
| | - Rose Njemini
- Department of Gerontology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium; Frailty in Ageing Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium.
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27
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Andrs M, Stoy H, Boleslavska B, Chappidi N, Kanagaraj R, Nascakova Z, Menon S, Rao S, Oravetzova A, Dobrovolna J, Surendranath K, Lopes M, Janscak P. Excessive reactive oxygen species induce transcription-dependent replication stress. Nat Commun 2023; 14:1791. [PMID: 36997515 PMCID: PMC10063555 DOI: 10.1038/s41467-023-37341-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 03/10/2023] [Indexed: 04/03/2023] Open
Abstract
Elevated levels of reactive oxygen species (ROS) reduce replication fork velocity by causing dissociation of the TIMELESS-TIPIN complex from the replisome. Here, we show that ROS generated by exposure of human cells to the ribonucleotide reductase inhibitor hydroxyurea (HU) promote replication fork reversal in a manner dependent on active transcription and formation of co-transcriptional RNA:DNA hybrids (R-loops). The frequency of R-loop-dependent fork stalling events is also increased after TIMELESS depletion or a partial inhibition of replicative DNA polymerases by aphidicolin, suggesting that this phenomenon is due to a global replication slowdown. In contrast, replication arrest caused by HU-induced depletion of deoxynucleotides does not induce fork reversal but, if allowed to persist, leads to extensive R-loop-independent DNA breakage during S-phase. Our work reveals a link between oxidative stress and transcription-replication interference that causes genomic alterations recurrently found in human cancer.
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Affiliation(s)
- Martin Andrs
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Henriette Stoy
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Barbora Boleslavska
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Faculty of Science, Charles University in Prague, Prague, Czech Republic
| | - Nagaraja Chappidi
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
- Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Radhakrishnan Kanagaraj
- Genome Engineering Laboratory, School of Life Sciences, University of Westminster, London, UK
- School of Life Sciences, University of Bedfordshire, Luton, UK
- Centre for Drug Discovery and Development, Sathyabama Institute of Science and Technology, Chennai, India
| | - Zuzana Nascakova
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Shruti Menon
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
- School of Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA
| | - Satyajeet Rao
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Anna Oravetzova
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Faculty of Science, Charles University in Prague, Prague, Czech Republic
| | - Jana Dobrovolna
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kalpana Surendranath
- Genome Engineering Laboratory, School of Life Sciences, University of Westminster, London, UK
- Centre for Drug Discovery and Development, Sathyabama Institute of Science and Technology, Chennai, India
| | - Massimo Lopes
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Pavel Janscak
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
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28
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Khalil R, Diab-Assaf M, Lemaitre JM. Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies. Cells 2023; 12:915. [PMID: 36980256 PMCID: PMC10047596 DOI: 10.3390/cells12060915] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/19/2023] Open
Abstract
Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by "senolytics" or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities.
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Affiliation(s)
- Roula Khalil
- IRMB, University Montpellier, INSERM, 34090 Montpellier, France;
| | - Mona Diab-Assaf
- Fanar Faculty of Sciences II, Lebanese University, Beirut P.O. Box 90656, Lebanon;
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29
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Kim TW. Targeting ER Stress with Saikosaponin A to Overcome Resistance under Radiation in Gastric Cancer Cells. Int J Mol Sci 2023; 24:ijms24065661. [PMID: 36982736 PMCID: PMC10052548 DOI: 10.3390/ijms24065661] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 03/18/2023] Open
Abstract
Saikosaponin A is a triterpene saponin and a potentially bioactive compound derived from Bupleurum falcatum L. However, the molecular mechanisms and effects of saikosaponin A in gastric cancer remain unknown. In the present study, I evaluated the effects of saikosaponin A on cell death and endoplasmic reticulum stress via calcium and reactive oxygen species release. Targeting reactive oxygen species with diphenyleneiodonium and N-acetylcysteine inhibited cell death and protein kinase RNA-like ER kinase signaling pathway by down-regulating Nox4 and inducing glucose-regulated protein 78 exosomes. Furthermore, saikosaponin A caused a synergistic inhibitory effect of the epithelial mesenchymal transition phenomenon, indicating the reversible phenotype modulation by epithelial cells under radiation exposure in radiation-resistant gastric cancer cells. These results suggest that saikosaponin A-mediated calcium and reactive oxygen species-induced endoplasmic reticulum stress overcome radio-resistance and induce cell death under radiation in gastric cancer cells. Therefore, saikosaponin A in combination with radiation may be a potential strategy for gastric cancer therapy.
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Affiliation(s)
- Tae Woo Kim
- Department of Biopharmaceutical Engineering, Dongguk University-WISE, Gyeongju 38066, Gyeongbuk, Republic of Korea
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30
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Martini H, Passos JF. Cellular senescence: all roads lead to mitochondria. FEBS J 2023; 290:1186-1202. [PMID: 35048548 PMCID: PMC9296701 DOI: 10.1111/febs.16361] [Citation(s) in RCA: 147] [Impact Index Per Article: 73.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/11/2022] [Accepted: 01/18/2022] [Indexed: 01/10/2023]
Abstract
Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the senescence-associated secretory phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.
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Affiliation(s)
- Hélène Martini
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905 USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, 55905 USA
| | - João F. Passos
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905 USA
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, 55905 USA
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Haq MFU, Hussain MZ, Mahjabeen I, Akram Z, Saeed N, Shafique R, Abbasi SF, Kayani MA. Oncometabolic role of mitochondrial sirtuins in glioma patients. PLoS One 2023; 18:e0281840. [PMID: 36809279 PMCID: PMC9943017 DOI: 10.1371/journal.pone.0281840] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/31/2023] [Indexed: 02/23/2023] Open
Abstract
Mitochondrial sirtuins have diverse role specifically in aging, metabolism and cancer. In cancer, these sirtuins play dichotomous role as tumor suppressor and promoter. Previous studies have reported the involvement of sirtuins in different cancers. However, till now no study has been published with respect to mitochondrial sirtuins and glioma risks. Present study was purposed to figure out the expression level of mitochondrial sirtuins (SIRT3, SIRT4, SIRT5) and related genes (GDH, OGG1-2α, SOD1, SOD2, HIF1α and PARP1) in 153 glioma tissue samples and 200 brain tissue samples from epilepsy patients (taken as controls). To understand the role of selected situins in gliomagenesis, DNA damage was measured using the comet assay and oncometabolic role (oxidative stress level, ATP level and NAD level) was measured using the ELISA and quantitative PCR. Results analysis showed significant down-regulation of SIRT4 (p = 0.0337), SIRT5 (p<0.0001), GDH (p = 0.0305), OGG1-2α (p = 0.0001), SOD1 (p<0.0001) and SOD2 (p<0.0001) in glioma patients compared to controls. In case of SIRT3 (p = 0.0322), HIF1α (p = 0.0385) and PARP1 (p = 0.0203), significant up-regulation was observed. ROC curve analysis and cox regression analysis showed the good diagnostic and prognostic value of mitochondrial sirtuins in glioma patients. Oncometabolic rate assessment analysis showed significant increased ATP level (p<0.0001), NAD+ level [(NMNAT1 (p<0.0001), NMNAT3 (p<0.0001) and NAMPT (p<0.04)] and glutathione level (p<0.0001) in glioma patients compared to controls. Significant increased level of damage ((p<0.04) and decrease level of antioxidant enzymes include superoxide dismutase (SOD, p<0.0001), catalase (CAT, p<0.0001) and glutathione peroxidase (GPx, p<0.0001) was observed in patients compared to controls. Present study data suggest that variation in expression pattern of mitochondrial sirtuins and increased metabolic rate may have diagnostic and prognostic significance in glioma patients.
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Affiliation(s)
- Maria Fazal Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
- * E-mail:
| | - Zertashia Akram
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Rabia Shafique
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Sumaira Fida Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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Han C, Deng Y, Yang B, Hu P, Hu B, Wang T, Liu J, Xia Q, Liu X. Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer. Front Immunol 2023; 14:1126902. [PMID: 36891298 PMCID: PMC9986540 DOI: 10.3389/fimmu.2023.1126902] [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: 12/18/2022] [Accepted: 02/01/2023] [Indexed: 02/22/2023] Open
Abstract
Background Prostate cancer (PCa) is an age-associated malignancy with high morbidity and mortality rate, posing a severe threat to public health. Cellular senescence, a specialized cell cycle arrest form, results in the secretion of various inflammatory mediators. In recent studies, senescence has shown an essential role in tumorigenesis and tumor development, yet the extensive effects of senescence in PCa have not been systematically investigated. Here, we aimed to develop a feasible senescence-associated prognosis model for early identification and appropriate management in patients with PCa. Method The RNA sequence results and clinical information available from The Cancer Genome Atlas (TCGA) and a list of experimentally validated senescence-related genes (SRGs) from the CellAge database were first obtained. Then, a senescence-risk signature related with prognosis was constructed using univariate Cox and LASSO regression analysis. We calculated the risk score of each patient and divided them into high-risk and low-risk groups in terms of the median value. Furthermore, two datasets (GSE70770 and GSE46602) were used to assess the effects of the risk model. A nomogram was built by integrating the risk score and clinical characteristics, which was further verified using ROC curves and calibrations. Finally, we compared the differences in the tumor microenvironment (TME) landscape, drug susceptibility, and the functional enrichment among the different risk groups. Results We established a unique prognostic signature in PCa patients based on eight SRGs, including CENPA, ADCK5, FOXM1, TFAP4, MAPK, LGALS3, BAG3, and NOX4, and validated well prognosis-predictive power in independent datasets. The risk model was associated with age and TNM staging, and the calibration chart presented a high consistency in nomogram prediction. Additionally, the prognostic signature could serve as an independent prediction factor due to its high accuracy. Notably, we found that the risk score was positively associated with tumor mutation burden (TMB) and immune checkpoint, whereas negatively correlated with tumor immune dysfunction and exclusion (TIDE), suggesting that these patients with risk scores were more sensitive to immunotherapy. Drug susceptibility analysis revealed differences in the responses to general drugs (docetaxel, cyclophosphamide, 5-Fluorouracil, cisplatin, paclitaxel, and vincristine) were yielded between the two risk groups. Conclusion Identifying the SRG-score signature may become a promising method for predicting the prognosis of patients with PCa and tailoring appropriate treatment strategies.
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Affiliation(s)
- Chenglin Han
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuxuan Deng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Yang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bintao Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qidong Xia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Oxidative Stress Correlates with More Aggressive Features in Thyroid Cancer. Cancers (Basel) 2022; 14:cancers14235857. [PMID: 36497339 PMCID: PMC9737385 DOI: 10.3390/cancers14235857] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 11/30/2022] Open
Abstract
Oxidative stress (OS) can have an impact in the pathogenesis and in the progression of thyroid cancer. We investigated the levels of reactive oxygen species (ROS) in 50 malignant and benign thyroid lesions and 41 normal tissues, and correlated them with the thyroid differentiation score-TDS and the clinico-pathologic features. NOX4 expression, GPx activity and the genetic pattern of tumors were evaluated. In malignant and benign lesions, ROS generation and NOX4 protein expression were higher than in normal tissues. Follicular (FTCs) and anaplastic/poorly differentiated cancers had increased OS relative to papillary tumors (PTCs). Moreover, OS in FTCs was higher than in follicular adenomas. Mutated PTCs showed increased OS compared with non-mutated PTCs. In malignant tumors, OS was inversely correlated with TDS, and directly correlated with tumor stage and ATA risk. GPx activity was increased in tumors compared with normal tissues, and inversely correlated to OS. In conclusion, our data indicate that thyroid tumors are exposed to higher OS compared with normal tissues, while showing a compensative increased GPx activity. OS correlates with tumor aggressiveness and mutations in the MEK-ERK pathway in PTC. The inverse correlation between OS and TDS suggests that ROS may repress genes involved in thyroid differentiation.
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NOX as a Therapeutic Target in Liver Disease. Antioxidants (Basel) 2022; 11:antiox11102038. [PMID: 36290761 PMCID: PMC9598239 DOI: 10.3390/antiox11102038] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022] Open
Abstract
The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease's progression.
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Salma F, Yassire O, Youssef B, Corinne D, Ameziane El Hassani R. Methods for detection of mitochondrial reactive oxygen species in senescent cells. Methods Cell Biol 2022; 181:33-41. [PMID: 38302242 DOI: 10.1016/bs.mcb.2022.09.011] [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: 11/06/2022]
Abstract
Cellular senescence is a pathophysiological process with multifaceted effects. It is involved in wound healing, aging and age-related diseases as well as cancer. On the one hand, senescence is considered as barrier against tumorigenesis by inducing an irreversible/prolonged cell cycle arrest. On the other hand, it may promote tumorigenesis when senescent cells accumulate genomic instability and bypass this cell cycle arrest. Interestingly, the bystander effects mediate the propagation of the genetic instability from senescent cells to their environment through the SASP (Senescence Associated Secretory Phenotype) including proinflammatory cytokines, proteases, growth factors and Reactive Oxygen Species 'ROS.' From several markers explored to detect senescent cells (β-galactosidase, p16, p21, p53, heterochromatin foci, DNA damage,…), ROS arouse particular interest because of their involvement at the chronic supraphysiological level, in the induction and maintain of DNA damage, inflammation, cell cycle disruption and epigenetic instability. In this context, the choice of methods to detect ROS in senescent cells is of particular interest and must take into account relevant parameters as well as the specificity for each species of ROS and the subcellular localization of ROS production. In this chapter, we introduce senescence and ROS, we briefly discuss the advantages and the shortcomings of methods routinely used to detect ROS. In addition, we describe the protocol to detect ROS at mitochondrial level (using the MitoSOX staining) in the BCPAP cell line (from human papillary thyroid carcinomas) expressing BRAFV600E oncogene known to trigger senescence.
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Affiliation(s)
- Fenniche Salma
- BioPatH Laboratory, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco; Genome Integrity and Cancers, UMR 8200/9019 CNRS, Paris-Saclay University, Gustave Roussy, Villejuif, France
| | - Oubaddou Yassire
- BioPatH Laboratory, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco
| | - Bakri Youssef
- BioPatH Laboratory, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco
| | - Dupuy Corinne
- Genome Integrity and Cancers, UMR 8200/9019 CNRS, Paris-Saclay University, Gustave Roussy, Villejuif, France
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Vickridge E, Faraco CCF, Tehrani PS, Ramdzan ZM, Djerir B, Rahimian H, Leduy L, Maréchal A, Gingras AC, Nepveu A. The DNA repair function of BCL11A suppresses senescence and promotes continued proliferation of triple-negative breast cancer cells. NAR Cancer 2022; 4:zcac028. [PMID: 36186110 PMCID: PMC9516615 DOI: 10.1093/narcan/zcac028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/08/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
We identified the BCL11A protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro, DNA repair assays demonstrate that both BCL11A and a small recombinant BCL11A160-520 protein that is devoid of DNA binding and transcription regulatory domains can stimulate the enzymatic activities of two base excision repair enzymes: NTHL1 and DNA Pol β. Increased DNA repair efficiency, in particular of the base excision repair pathway, is essential for many cancer cells to proliferate in the presence of elevated reactive oxygen species (ROS) produced by cancer-associated metabolic changes. BCL11A is highly expressed in triple-negative breast cancers (TNBC) where its knockdown was reported to reduce clonogenicity and cause tumour regression. We show that BCL11A knockdown in TNBC cells delays repair of oxidative DNA damage, increases the number of oxidized bases and abasic sites in genomic DNA, slows down proliferation and induces cellular senescence. These phenotypes are rescued by ectopic expression of the short BCL11A160-520 protein. We further show that the BCL11A160-520 protein accelerates the repair of oxidative DNA damage and cooperates with RAS in cell transformation assays, thereby enabling cells to avoid senescence and continue to proliferate in the presence of high ROS levels.
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Affiliation(s)
- Elise Vickridge
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Camila C F Faraco
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Payman S Tehrani
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Zubaidah M Ramdzan
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Billel Djerir
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - Hedyeh Rahimian
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Lam Leduy
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Alexandre Maréchal
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Alain Nepveu
- To whom correspondence should be addressed. Tel: +1 514 398 5839; Fax: +1 514 398 6769;
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Sanati M, Afshari AR, Kesharwani P, Sukhorukov VN, Sahebkar A. Recent trends in the application of nanoparticles in cancer therapy: The involvement of oxidative stress. J Control Release 2022; 348:287-304. [PMID: 35644289 DOI: 10.1016/j.jconrel.2022.05.035] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/17/2022] [Accepted: 05/21/2022] [Indexed: 12/15/2022]
Abstract
In the biomedical area, the interdisciplinary field of nanotechnology has the potential to bring numerous unique applications, including better tactics for cancer detection, diagnosis, and therapy. Nanoparticles (NPs) have been the topic of many research and material applications throughout the last decade. Unlike small-molecule medications, NPs are defined by distinct physicochemical characteristics, such as a large surface-to-volume ratio, which allows them to permeate live cells with relative ease. The versatility of NPs as both therapeutics and diagnostics makes them ideal for a broad spectrum of illnesses, from infectious diseases to cancer. A significant amount of data has been participated in the current scientific publications, emphasizing the concept that NPs often produce reactive oxygen species (ROS) to a larger degree than micro-sized particles. It is important to note that oxidative stress governs a wide range of cell signaling cascades, many of which are responsible for cancer cell cytotoxicity. Here, we aimed to provide insight into the signaling pathways triggered by oxidative stress in cancer cells in response to several types of nanomaterials, such as metallic and polymeric NPs and quantum dots. We discuss recent advances in developing integrated anticancer medicines based on NPs targeted to destroy malignant cells by increasing their ROS setpoint.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran; Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Vasily N Sukhorukov
- Avtsyn Research Institute of Human Morphology of FSBI "Petrovsky National Research Centre of Surgery", Moscow, Russia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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38
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Vickridge E, Faraco CCF, Nepveu A. Base excision repair accessory factors in senescence avoidance and resistance to treatments. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:703-720. [PMID: 36176767 PMCID: PMC9511810 DOI: 10.20517/cdr.2022.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 06/16/2023]
Abstract
Cancer cells, in which the RAS and PI3K pathways are activated, produce high levels of reactive oxygen species (ROS), which cause oxidative DNA damage and ultimately cellular senescence. This process has been documented in tissue culture, mouse models, and human pre-cancerous lesions. In this context, cellular senescence functions as a tumour suppressor mechanism. Some rare cancer cells, however, manage to adapt to avoid senescence and continue to proliferate. One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor. In this review, we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS: the increased activity of the base excision repair (BER) pathway, achieved through the enhanced expression of BER enzymes and DNA repair accessory factors. These proteins, exemplified here by the CUT domain proteins CUX1, CUX2, and SATB1, stimulate the activity of BER enzymes. The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels. As a by-product of this adaptation, these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation, temozolomide, and cisplatin. Moreover, considering the intrinsic error rate associated with DNA repair and translesion synthesis, the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population, thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance, a major obstacle to clinical treatment.
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Affiliation(s)
- Elise Vickridge
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- These authors contributed equally to this work
| | - Camila C. F. Faraco
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- These authors contributed equally to this work
| | - Alain Nepveu
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Medicine, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Oncology, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
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Redox Homeostasis in Thyroid Cancer: Implications in Na +/I - Symporter (NIS) Regulation. Int J Mol Sci 2022; 23:ijms23116129. [PMID: 35682803 PMCID: PMC9181215 DOI: 10.3390/ijms23116129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/17/2022] [Accepted: 05/27/2022] [Indexed: 02/04/2023] Open
Abstract
Radioiodine therapy (RAI) is a standard and effective therapeutic approach for differentiated thyroid cancers (DTCs) based on the unique capacity for iodide uptake and accumulation of the thyroid gland through the Na+/I− symporter (NIS). However, around 5–15% of DTC patients may become refractory to radioiodine, which is associated with a worse prognosis. The loss of RAI avidity due to thyroid cancers is attributed to cell dedifferentiation, resulting in NIS repression by transcriptional and post-transcriptional mechanisms. Targeting the signaling pathways potentially involved in this process to induce de novo iodide uptake in refractory tumors is the rationale of “redifferentiation strategies”. Oxidative stress (OS) results from the imbalance between ROS production and depuration that favors a pro-oxidative environment, resulting from increased ROS production, decreased antioxidant defenses, or both. NIS expression and function are regulated by the cellular redox state in cancer and non-cancer contexts. In addition, OS has been implicated in thyroid tumorigenesis and thyroid cancer cell dedifferentiation. Here, we review the main aspects of redox homeostasis in thyrocytes and discuss potential ROS-dependent mechanisms involved in NIS repression in thyroid cancer.
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40
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Synergistic antitumor effect of Andrographolide and cisplatin through ROS-mediated ER stress and STAT3 inhibition in colon cancer. Med Oncol 2022; 39:101. [DOI: 10.1007/s12032-022-01691-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/21/2022] [Indexed: 11/25/2022]
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Fielder E, Wan T, Alimohammadiha G, Ishaq A, Low E, Weigand BM, Kelly G, Parker C, Griffin B, Jurk D, Korolchuk VI, von Zglinicki T, Miwa S. Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice. eLife 2022; 11:75492. [PMID: 35507395 PMCID: PMC9154747 DOI: 10.7554/elife.75492] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 05/03/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesise that therapy-induced senescence and senescence progression via bystander effects are significant causes of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sublethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow-up was for 1 year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations, metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial reactive oxygen species production via NADPH oxidase 4 inhibition in senescent cells. Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.
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Affiliation(s)
- Edward Fielder
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Tengfei Wan
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Ghazaleh Alimohammadiha
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Abbas Ishaq
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Evon Low
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - B Melanie Weigand
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - George Kelly
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Craig Parker
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Brigid Griffin
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Diana Jurk
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Viktor I Korolchuk
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Thomas von Zglinicki
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
| | - Satomi Miwa
- Newcastle University Biosciences Institute, Newcastle University, Newcastle upon Tyne, Newcastle, United Kingdom
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Coelho de Faria C, Hecht Castro Medeiros F, Cazarin Menezes J, Ortenzi de Andrade Silva VH, Freitas Ferreira AC, Pires de Carvalho D, Soares Fortunato R. TGF-β1 Disrupts redox balance in PCCL3 thyroid cell and is sexually dimorphic expressed in rat thyroid gland. Mol Cell Endocrinol 2022; 546:111593. [PMID: 35139422 DOI: 10.1016/j.mce.2022.111593] [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: 12/29/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 11/26/2022]
Abstract
Thyroid diseases are more prevalent in women, and this difference seems to be associated with the oxidative stress found in the thyroid of females. Thyroid NADPH Oxidase 4 (NOX4) was shown to respond to estrogen, which can also modulate TGF-β1, a potent stimulator of NOX4. This study aimed to investigate the effects of TGF-β1 on redox homeostasis parameters in the rat thyroid cell PCCL3 and the interrelationship between estrogen and TGF-β1. TGF-β1 treatment increased both intra- and extracellular ROS generation along with NOX4 expression and reduced GPX and catalase activities, extracellular H2O2 scavenging capacity, and reduced thiol content. TGF-β1 mRNA and protein expression are higher in female thyroid glands of rats in comparison to males. Moreover, 17β-estradiol treatment enhanced TGF-β1 mRNA in PCCL3 cells, decreased extracellular bioavailability but did not activate Smad pathway. Our data suggest that higher levels of TGF-β1 in females are potentially related to higher ROS availability which may be associated with the sex disparity in thyroid disorders.
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Affiliation(s)
- Caroline Coelho de Faria
- Laboratório de Fisiologia e Sinalização Redox, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G2-042, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil
| | - Fabio Hecht Castro Medeiros
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G1-060, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil
| | - Juliana Cazarin Menezes
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G1-060, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil
| | - Victor Hugo Ortenzi de Andrade Silva
- Laboratório de Fisiologia e Sinalização Redox, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G2-042, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil
| | - Andrea Claudia Freitas Ferreira
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G1-060, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil; NUMPEX, Pólo de Xerém, Universidade Federal do Rio de Janeiro, Brazil
| | - Denise Pires de Carvalho
- Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G1-060, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil
| | - Rodrigo Soares Fortunato
- Laboratório de Fisiologia e Sinalização Redox, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Bloco G, sala G2-042, Av. Carlos Chagas Filho, 373, 21941-902, Rio de Janeiro, Brazil.
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Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53. Oncogene 2022; 41:2719-2733. [PMID: 35393546 PMCID: PMC9076537 DOI: 10.1038/s41388-022-02291-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 11/09/2022]
Abstract
Cancer cells often experience high basal levels of DNA replication stress (RS), for example due to hyperactivation of oncoproteins like MYC or RAS. Therefore, cancer cells are considered to be sensitive to drugs that exacerbate the level of RS or block the intra S-phase checkpoint. Consequently, RS-inducing drugs including ATR and CHK1 inhibitors are used or evaluated as anti-cancer therapies. However, drug resistance and lack of biomarkers predicting therapeutic efficacy limit efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS does not only enhance the sensitivity to ATR/CHK1 inhibitors by directly causing RS. Instead, we observed that HRASG12V dampens the activation of the P53-dependent transcriptional response to drug-induced RS, which in turn confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V sensitized cells to ATR and CHK1 inhibitors. Using RNA-sequencing of FACS-sorted cells we discovered that P53 signaling is the sole transcriptional response to RS. However, oncogenic RAS attenuates the transcription of P53 and TGF-β pathway components which consequently dampens P53 target gene expression. Accordingly, live cell imaging showed that HRASG12V exacerbates RS in S/G2-phase, which could be rescued by stabilization of P53. Thus, our results demonstrate that transcriptional control of P53 target genes is the prime determinant in the response to ATR/CHK1 inhibitors and show that hyperactivation of the MAPK pathway impedes this response. Our findings suggest that the level of oncogenic MAPK signaling could predict sensitivity to intra-S-phase checkpoint inhibition in cancers with intact P53.
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Chavda V, Chaurasia B, Garg K, Deora H, Umana GE, Palmisciano P, Scalia G, Lu B. Molecular mechanisms of oxidative stress in stroke and cancer. BRAIN DISORDERS 2022. [DOI: 10.1016/j.dscb.2021.100029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Szanto I. NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation. Int J Mol Sci 2022; 23:ijms23052702. [PMID: 35269843 PMCID: PMC8910662 DOI: 10.3390/ijms23052702] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
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Affiliation(s)
- Ildiko Szanto
- Service of Endocrinology, Diabetology, Nutrition and Patient Education, Department of Internal Medicine, Geneva University Hospitals, Diabetes Center of the Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
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Possible actions of cannabidiol in obsessive-compulsive disorder by targeting the WNT/β-catenin pathway. Mol Psychiatry 2022; 27:230-248. [PMID: 33837269 DOI: 10.1038/s41380-021-01086-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/13/2021] [Accepted: 03/26/2021] [Indexed: 02/02/2023]
Abstract
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and glutamatergic pathways play key roles in the causes of OCD. However, first-line therapies include cognitive-behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for new treatment is mandatory. This review focuses on the potential effects of cannabidiol (CBD), as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which CBD provides its benefit properties. CBD medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway and circadian rhythms dysregulation in OCD. Future prospective clinical trials could focus on CBD and its different and multiple interactions in OCD.
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miR-199a Downregulation as a Driver of the NOX4/HIF-1α/VEGF-A Pathway in Thyroid and Orbital Adipose Tissues from Graves′ Patients. Int J Mol Sci 2021; 23:ijms23010153. [PMID: 35008579 PMCID: PMC8745087 DOI: 10.3390/ijms23010153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/14/2021] [Accepted: 12/22/2021] [Indexed: 12/20/2022] Open
Abstract
Graves’ disease (GD) is an autoimmune thyroiditis often associated with Graves’ orbitopathy (GO). GD thyroid and GO orbital fat share high oxidative stress (OS) and hypervascularization. We investigated the metabolic pathways leading to OS and angiogenesis, aiming to further decipher the link between local and systemic GD manifestations. Plasma and thyroid samples were obtained from patients operated on for multinodular goiters (controls) or GD. Orbital fats were from GO or control patients. The NADPH-oxidase-4 (NOX4)/HIF-1α/VEGF-A signaling pathway was investigated by Western blotting and immunostaining. miR-199a family expression was evaluated following quantitative real-time PCR and/or in situ hybridization. In GD thyroids and GO orbital fats, NOX4 was upregulated and correlated with HIF-1α stabilization and VEGF-A overexpression. The biotin assay identified NOX4, HIF-1α and VEGF-A as direct targets of miR-199a-5p in cultured thyrocytes. Interestingly, GD thyroids, GD plasmas and GO orbital fats showed a downregulation of miR-199a-3p/-5p. Our results also highlighted an activation of STAT-3 signaling in GD thyroids and GO orbital fats, a transcription factor known to negatively regulate miR-199a expression. We identified NOX4/HIF-1α/VEGF-A as critical actors in GD and GO. STAT-3-dependent regulation of miR-199a is proposed as a common driver leading to these events in GD thyroids and GO orbital fats.
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Salovska B, Kondelova A, Pimkova K, Liblova Z, Pribyl M, Fabrik I, Bartek J, Vajrychova M, Hodny Z. Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape. Redox Biol 2021; 49:102212. [PMID: 34923300 PMCID: PMC8688892 DOI: 10.1016/j.redox.2021.102212] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 12/31/2022] Open
Abstract
Cellular senescence is a complex stress response defined as an essentially irreversible cell cycle arrest mediated by the inhibition of cell cycle-specific cyclin dependent kinases. The imbalance in redox homeostasis and oxidative stress have been repeatedly observed as one of the hallmarks of the senescent phenotype. However, a large-scale study investigating protein oxidation and redox signaling in senescent cells in vitro has been lacking. Here we applied a proteome-wide analysis using SILAC-iodoTMT workflow to quantitatively estimate the level of protein sulfhydryl oxidation and proteome level changes in ionizing radiation-induced senescence (IRIS) in hTERT-RPE-1 cells. We observed that senescent cells mobilized the antioxidant system to buffer the increased oxidation stress. Among the antioxidant proteins with increased relative abundance in IRIS, a unique 1-Cys peroxiredoxin family member, peroxiredoxin 6 (PRDX6), was identified as an important contributor to protection against oxidative stress. PRDX6 silencing increased ROS production in senescent cells, decreased their resistance to oxidative stress-induced cell death, and impaired their viability. Subsequent SILAC-iodoTMT and secretome analysis after PRDX6 silencing showed the downregulation of PRDX6 in IRIS affected protein secretory pathways, decreased expression of extracellular matrix proteins, and led to unexpected attenuation of senescence-associated secretory phenotype (SASP). The latter was exemplified by decreased secretion of pro-inflammatory cytokine IL-6 which was also confirmed after treatment with an inhibitor of PRDX6 iPLA2 activity, MJ33. In conclusion, by combining different methodological approaches we discovered a novel role of PRDX6 in senescent cell viability and SASP development. Our results suggest PRDX6 could have a potential as a drug target for senolytic or senomodulatory therapy.
SILAC-iodoTMT is a powerful tool to quantify redox imbalance in IRIS. Senescence in hTERT-RPE-1 cells is not accompanied by bulk cysteine oxidation. Antioxidant proteins are upregulated in senescent hTERT-RPE-1 cells. PRDX6 silencing affects redox homeostasis and viability of senescent cells. PRDX6 silencing alters secretome of senescent RPE-1 cells and suppresses IL-6.
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Affiliation(s)
- Barbora Salovska
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Alexandra Kondelova
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kristyna Pimkova
- Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; BIOCEV, 1st Medical Faculty, Charles University, Vestec, Czech Republic
| | - Zuzana Liblova
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Miroslav Pribyl
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Ivo Fabrik
- Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Jiri Bartek
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
| | - Marie Vajrychova
- Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
| | - Zdenek Hodny
- Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
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Roger L, Tomas F, Gire V. Mechanisms and Regulation of Cellular Senescence. Int J Mol Sci 2021; 22:ijms222313173. [PMID: 34884978 PMCID: PMC8658264 DOI: 10.3390/ijms222313173] [Citation(s) in RCA: 193] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/25/2021] [Accepted: 12/02/2021] [Indexed: 12/23/2022] Open
Abstract
Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.
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Affiliation(s)
- Lauréline Roger
- Structure and Instability of Genomes Laboratory, Muséum National d’Histoire Naturelle (MNHN), CNRS-UMR 7196/INSERM U1154, 43 Rue Cuvier, 75005 Paris, France;
| | - Fanny Tomas
- Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier, CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier, France;
| | - Véronique Gire
- Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier, CNRS UMR 5237, 1919 Route de Mende, 34293 Montpellier, France;
- Correspondence: ; Tel.: +33-(0)-434359513; Fax: +33-(0)-434359410
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Protective Effect of Honey and Propolis against Gentamicin-Induced Oxidative Stress and Hepatorenal Damages. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9719906. [PMID: 34512873 PMCID: PMC8433017 DOI: 10.1155/2021/9719906] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/08/2021] [Accepted: 08/19/2021] [Indexed: 01/23/2023]
Abstract
Bee products are a promising source of phenolic compounds with strong antioxidant activity. The present study was designed to explore the protective effect of honey, propolis, and their combination on gentamicin-induced oxidative stress and hepatorenal dysfunction. This study was conducted on male Wistar rats by intraperitoneal injections of gentamicin (120 mg/kg BW/day, i.p.) or normal saline (1 ml/kg BW/day, i.p.) for 10 consecutive days. Honey (2 g/kg BW), propolis (100 mg/kg BW), or their combination were given daily by gavage to normal and gentamicin groups. Honey and propolis samples were evaluated for their phytochemical composition and antioxidant capacity. The in vitro investigations showed that the evaluated samples especially propolis extract have high antioxidant power associated with the presence of several phenolic compounds such as flavonoids, flavan-3-ols, hydroxybenzoic acids, hydroxycinnamic acids, and stilbenes, while honey contains only hydroxybenzoic acids and hydroxycinnamic acids. It was also shown that simultaneous treatment with honey or propolis extract alone or in association prevented changes caused by gentamicin administration and improved hepatic and renal functions. Changes caused by gentamicin administration, observed by in vivo experiments, include significant elevation of uric acid, urea, creatinine, and hepatic enzyme levels (ALT, AST, and ALP) and kidney biochemical changes (an increase of urea, uric acid, and creatinine and a decrease of albumin and total protein) as well as remarkable changes of renal and liver oxidative stress markers (CAT, GPx, and GSH) and elevation of MDA levels. Overall, it can be concluded that honey and propolis might be useful in the management of liver and renal diseases induced by xenobiotics.
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