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Terra L, Boekel NB, Hooning MH, Collee M, Schmidt MK, Adank MA, Kok M, Aleman BMP, Jager A, Sattler MGA, Maas AHEM, Schaapveld M, van Leeuwen FE. Cardiovascular disease risk after breast cancer treatment in patients with a BRCA1/2 pathogenic variant. Breast Cancer Res Treat 2025; 209:573-583. [PMID: 39482556 DOI: 10.1007/s10549-024-07516-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 10/03/2024] [Indexed: 11/03/2024]
Abstract
PURPOSE Breast cancer (BC) treatment can induce adverse events, such as cardiovascular disease (CVD). Defective DNA repair, as in carriers of BRCA1/2 pathogenic variants (BRCA1/2pv), may contribute to CVD risk. We aimed to study if female BRCA1/2pv carriers are more sensitive to develop CVD after BC treatment than BC patients without a known BRCA1/2pv. METHODS In a hospital-based cohort of 17,300 female BC patients, we identified 509 BRCA1/2pv carriers. Cardiovascular morbidity and mortality were assessed through hospital charts and general practitioner questionnaires. We performed Cox regression analyses comparing BRCA1/2pv carriers with all other BC patients, adjusting for age, radiotherapy regimen, chemotherapy regimen, and smoking status. RESULTS Median follow-up time since BC treatment was 14 years. In total, 1108 women experienced ischemic heart disease (IHD), of whom 20 (1.8%) were BRCA1/2pv carriers. Heart failure (HF) was diagnosed in 638 women, of whom 10 (1.6%) were BRCA1/2pv carriers. BRCA1/2pv carriership was associated with a slight not statistically significant increase of IHD (adjHR 1.51, 95%CI 0.93; 2.42), but not with risk of HF (adjHR 0.86, 95%CI 0.44; 1.69). The association between radiotherapy and IHD risk was not significantly different between BRCA1/2pv carriers [HR 2.30 (95%CI 0.79; 6.66)] and other BC patients (HR 1.50, 95%CI 1.30; 1.73). Associations between anthracycline-based chemotherapy and HF risk also did not differ between carriers and other BC patients (HRs of 4.02 (95%CI 1.02; 15.77) and 2.31 (95%CI 1.77; 3.01), respectively). CONCLUSIONS In BRCA1/2pv BC patients, we found no evidence for a higher risk of BC treatment-related CVD than in other BC patients.
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Affiliation(s)
- Lara Terra
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, CX, The Netherlands
| | - Naomi B Boekel
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, CX, The Netherlands
| | - Maartje H Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Margriet Collee
- Department of Clinical Genetics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Marjanka K Schmidt
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, CX, The Netherlands
- Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Muriel A Adank
- Clinical Genetics Department, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marleen Kok
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Berthe M P Aleman
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Agnes Jager
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Margriet G A Sattler
- Department of Radiotherapy, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Angela H E M Maas
- Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michael Schaapveld
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, CX, The Netherlands
| | - Flora E van Leeuwen
- Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, Amsterdam, CX, The Netherlands.
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Long Y, Shi H, Ye J, Qi X. Exploring Strategies to Prevent and Treat Ovarian Cancer in Terms of Oxidative Stress and Antioxidants. Antioxidants (Basel) 2025; 14:114. [PMID: 39857448 PMCID: PMC11762571 DOI: 10.3390/antiox14010114] [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: 11/27/2024] [Revised: 12/30/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Oxidative stress is a state of imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the antioxidant defence system in the body. Oxidative stress may be associated with a variety of diseases, such as ovarian cancer, diabetes mellitus, and neurodegeneration. The generation of oxidative stress in ovarian cancer, one of the common and refractory malignancies among gynaecological tumours, may be associated with several factors. On the one hand, the increased metabolism of ovarian cancer cells can lead to the increased production of ROS, and on the other hand, the impaired antioxidant defence system of ovarian cancer cells is not able to effectively scavenge the excessive ROS. In addition, chemotherapy and radiotherapy may elevate the oxidative stress in ovarian cancer cells. Oxidative stress can cause oxidative damage, promote the development of ovarian cancer, and even result in drug resistance. Therefore, studying oxidative stress in ovarian cancer is important for the prevention and treatment of ovarian cancer. Antioxidants, important markers of oxidative stress, might serve as one of the strategies for preventing and treating ovarian cancer. In this review, we will discuss the complex relationship between oxidative stress and ovarian cancer, as well as the role and therapeutic potential of antioxidants in ovarian cancer, thus guiding future research and clinical interventions.
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Affiliation(s)
| | | | | | - Xiaorong Qi
- Key Laboratory of Birth, Defects and Related Diseases of Women and Children, Department of Gynecology and Obstetrics, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China; (Y.L.); (H.S.); (J.Y.)
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Shah V, Lam HY, Leong CHM, Sakaizawa R, Shah JS, Kumar AP. Epigenetic Control of Redox Pathways in Cancer Progression. Antioxid Redox Signal 2025. [PMID: 39815993 DOI: 10.1089/ars.2023.0465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
Significance: Growing evidence indicates the importance of redox reactions homeostasis, mediated predominantly by reactive oxygen species (ROS) in influencing the development, differentiation, progression, metastasis, programmed cell death, tumor microenvironment, and therapeutic resistance of cancer. Therefore, reviewing the ROS-linked epigenetic changes in cancer is fundamental to understanding the progression and prevention of cancer. Recent Advances: We review in depth the molecular mechanisms involved in ROS-mediated epigenetic changes that lead to alteration of gene expression by altering DNA, modifying histones, and remodeling chromatin and noncoding RNA. Critical Issues: In cancerous cells, alterations of the gene-expression regulatory elements could be generated by the virtue of imbalance in tumor microenvironment. Various oxidizing agents and mitochondrial electron transport chain are the major pathways that generate ROS. ROS plays a key role in carcinogenesis by activating pro-inflammatory signaling pathways and DNA damage. This loss of ROS-mediated epigenetic regulation of the signaling pathways may promote tumorigenesis. We address all such aspects in this review. Future Directions: Developments in this growing field of epigenetics are expected to contribute to further our understanding of human health and diseases such as cancer and to test the clinical applications of redox-based therapy. Recent studies of the cancer-epigenetic landscape have revealed pervasive deregulation of the epigenetic factors in cancer. Thus, the study of interaction between ROS and epigenetic factors in cancer holds a great promise in the development of effective and targeted treatment modalities. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
- Vandit Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Charlene Hoi-Mun Leong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reo Sakaizawa
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jigna S Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Yang W, Xu S, Zhou M, Chan P. Aging-related biomarkers for the diagnosis of Parkinson's disease based on bioinformatics analysis and machine learning. Aging (Albany NY) 2024; 16:12191-12208. [PMID: 39264583 PMCID: PMC11424590 DOI: 10.18632/aging.205954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 04/22/2024] [Indexed: 09/13/2024]
Abstract
Parkinson's disease (PD) is a multifactorial disease that lacks reliable biomarkers for its diagnosis. It is now clear that aging is the greatest risk factor for developing PD. Therefore, it is necessary to identify novel biomarkers associated with aging in PD. In this study, we downloaded aging-related genes from the Human Ageing Gene Database. To screen and verify biomarkers for PD, we used whole-blood RNA-Seq data from 11 PD patients and 13 healthy control (HC) subjects as a training dataset and three datasets retrieved from the Gene Expression Omnibus (GEO) database as validation datasets. Using the limma package in R, 1435 differentially expressed genes (DEGs) were found in the training dataset. Of these genes, 29 genes were found to occur in both DEGs and 307 aging-related genes. By using machine learning algorithms (LASSO, RF, SVM, and RR), Venn diagrams, and LASSO regression, four of these genes were determined to be potential PD biomarkers; these were further validated in external validation datasets and by qRT-PCR in the peripheral blood mononuclear cells (PBMCs) of 10 PD patients and 10 HC subjects. Based on the biomarkers, a diagnostic model was developed that had reliable predictive ability for PD. Two of the identified biomarkers demonstrated a meaningful correlation with immune cell infiltration status in the PD patients and HC subjects. In conclusion, four aging-related genes were identified as robust diagnostic biomarkers and may serve as potential targets for PD therapeutics.
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Affiliation(s)
- Weiwei Yang
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Shengli Xu
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Ming Zhou
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Piu Chan
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disorders, Beijing, China
- Clinical Center for Parkinson's Disease, Capital Medical University, Beijing, China
- Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Parkinson Disease Center of Beijing Institute for Brain Disorders, Beijing, China
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Javakhishvili I, Mardaleishvili K, Buleishvili M, Mantskava M, Chkhikvishvili I, Kalmakhelidze S, Kipiani N, Sanikidze T. Possible link between familial susceptibility to cancer and the level of oxidative stress in thyroid cancer patients. Hered Cancer Clin Pract 2024; 22:15. [PMID: 39180118 PMCID: PMC11342469 DOI: 10.1186/s13053-024-00287-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 08/08/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Hereditary cancer is estimated to account for up to 10% of the worldwide cancer burden; 5% of all thyroid cancers are thought to be genetic. Inheritance of a deleterious mutation in genes associated with a high lifetime risk of developing cancer. Cancer-predisposing genes can promote the initiation and progression of thyroid cancer by enhancing the activation of major signaling pathways through oxidative stress mechanisms. AIM Identification of the possible link between familial susceptibility to cancer and the level of oxidative stress in thyroid cancer patients. METHODS Patients with thyroid cancer (with and without genetic predisposition) were investigated. Study participants were treated in Limited Liability Company (LLC) "Oncology Scientific Research Center" (Tbilisi, Georgia). The study group was collected between 2020 and 2021. In patients' blood, the thyroid hormones content (free Triiodothyronine (fFT3), free Thyroxine (fFT4), bound Triiodothyronine (FT3), bound Thyroxine (FT4), Thyroid-stimulating hormone (TSH)), and oxidative stress intensity (total activity of non-enzymatic antioxidant system (TAA) and the lipid peroxidation product, malondialdehyde (MDA), content) were investigated. RESULTS The difference in free and bound forms of T3 and T4 levels in the blood serum between patients with thyroid cancer (Group 2 and Group 3) and the control group (Group 1) was not statistically significant (F1,2=0.5, p1,2=0.8, F1,3=2.31, p1,3=0.16). In patients with thyroid cancer the TSH level significantly increased compared to the control group (Group 1) (TSH (mean ± Std error): Group 1- 1.21 ± 0.12, Group 2-2.45 ± 0.11 (F1,2=107, p1,2<0.001), Group 3-2.47 ± 0.17 (F1,3=150, p1,3<0.001)) and the MDA levels increased by 4-5 fold. In patients with thyroid cancer from families with cancer aggregation(Group 2), the level of TAA statistically significantly decreased (F1 - 2=200; p1 - 2<0.001), in patients without genetic predisposition to cancer(Group 3), the level of TAA did not change compared to the control (F1 - 3= 2.13; p1 - 3=0.15), CONCLUSIONS: Oxidative stress plays a critical role in tumorigenesis, and antioxidant/oxidant imbalance may contribute to the malignant transformation of normal tissue. In patients with familial susceptibility to cancer mutations of several genes, which are involved in the regulation of oxidative metabolism, may contribute to the disruption of the redox balance, increase the level of oxidative stress, and contribute to the development of thyroid cancer.
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Affiliation(s)
| | | | - Maka Buleishvili
- Department of Physics, Biophysics, Biomechanics and Informative Technologies of Tbilisi, State Medical University, Tbilisi, Georgia
- Caucasus International University, Tbilisi, Georgia
| | - Maia Mantskava
- Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
| | | | - Sophio Kalmakhelidze
- Beritashvili Center of Experimental Biomedicine, Tbilisi State Medical University, Tbilisi, Georgia
| | - Nina Kipiani
- Beritashvili Center of Experimental Biomedicine, Tbilisi State Medical University, Tbilisi, Georgia
| | - Tamar Sanikidze
- Department of Physics, Biophysics, Biomechanics and Informative Technologies of Tbilisi, State Medical University, Tbilisi, Georgia.
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Galli A, Bellè F, Fargnoli A, Caligo MA, Cervelli T. Functional Characterization of the Human BRCA1 ∆11 Splicing Isoforms in Yeast. Int J Mol Sci 2024; 25:7511. [PMID: 39062754 PMCID: PMC11276823 DOI: 10.3390/ijms25147511] [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: 06/15/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
BRCA1, a crucial tumor suppressor gene, has several splicing isoforms, including Δ9-11, Δ11, and Δ11q, which lack exon 11, coding for significant portions of the protein. These isoforms are naturally present in both normal and cancerous cells, exhibiting altered activity compared to the full-length BRCA1. Despite this, the impact on cancer risk of the germline intronic variants promoting the exclusive expression of these Δ11 isoforms remains uncertain. Consequently, they are classified as variants of uncertain significance (VUS), posing challenges for traditional genetic classification methods due to their rarity and complexity. Our research utilizes a yeast-based functional assay, previously validated for assessing missense BRCA1 variants, to compare the activity of the Δ11 splicing isoforms with known pathogenic missense variants. This approach allows us to elucidate the functional implications of these isoforms and determine whether their exclusive expression could contribute to increased cancer risk. By doing so, we aim to provide insights into the pathogenic potential of intronic VUS-generating BRCA1 splicing isoforms and improve the classification of BRCA1 variants.
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Affiliation(s)
- Alvaro Galli
- Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (A.G.); (F.B.); (A.F.)
| | - Francesca Bellè
- Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (A.G.); (F.B.); (A.F.)
| | - Arcangelo Fargnoli
- Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (A.G.); (F.B.); (A.F.)
| | - Maria Adelaide Caligo
- Molecular Genetics Unit, Department of Oncology, University Hospital of Pisa, 56126 Pisa, Italy;
| | - Tiziana Cervelli
- Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (A.G.); (F.B.); (A.F.)
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7
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Bel’skaya LV, Dyachenko EI. Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production. Curr Issues Mol Biol 2024; 46:4646-4687. [PMID: 38785550 PMCID: PMC11120394 DOI: 10.3390/cimb46050282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024] Open
Abstract
This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
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8
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Xu L, Cao Y, Xu Y, Li R, Xu X. Redox-Responsive Polymeric Nanoparticle for Nucleic Acid Delivery and Cancer Therapy: Progress, Opportunities, and Challenges. Macromol Biosci 2024; 24:e2300238. [PMID: 37573033 DOI: 10.1002/mabi.202300238] [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: 05/25/2023] [Revised: 07/25/2023] [Indexed: 08/14/2023]
Abstract
Cancer development and progression of cancer are closely associated with the activation of oncogenes and loss of tumor suppressor genes. Nucleic acid drugs (e.g., siRNA, mRNA, and DNA) are widely used for cancer therapy due to their specific ability to regulate the expression of any cancer-associated genes. However, nucleic acid drugs are negatively charged biomacromolecules that are susceptible to serum nucleases and cannot cross cell membrane. Therefore, specific delivery tools are required to facilitate the intracellular delivery of nucleic acid drugs. In the past few decades, a variety of nanoparticles (NPs) are designed and developed for nucleic acid delivery and cancer therapy. In particular, the polymeric NPs in response to the abnormal redox status in cancer cells have garnered much more attention as their potential in redox-triggered nanostructure dissociation and rapid intracellular release of nucleic acid drugs. In this review, the important genes or signaling pathways regulating the abnormal redox status in cancer cells are briefly introduced and the recent development of redox-responsive NPs for nucleic acid delivery and cancer therapy is systemically summarized. The future development of NPs-mediated nucleic acid delivery and their challenges in clinical translation are also discussed.
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Affiliation(s)
- Lei Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Yuan Cao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Ya Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
| | - Rong Li
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, P. R. China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, P. R. China
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Jang Y, Koh JS, Park JH, Choi S, Duong PTT, Heo BY, Lee SW, Kim JY, Lee MW, Kim SH, Song IC. Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia. Int J Mol Sci 2024; 25:2140. [PMID: 38396817 PMCID: PMC10888725 DOI: 10.3390/ijms25042140] [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: 11/29/2023] [Revised: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.
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Affiliation(s)
- Yunseon Jang
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jeong Suk Koh
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Jung-Hyun Park
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Suyoung Choi
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Pham Thi Thuy Duong
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Bu Yeon Heo
- Brain Korea 21 FOUR Project for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Sang Woo Lee
- Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jung Yeon Kim
- Research Institute for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Myung-Won Lee
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Seok-Hwan Kim
- Research Institute for Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Surgery, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Ik-Chan Song
- Translational Immunology Institute, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
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10
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Iqbal MJ, Kabeer A, Abbas Z, Siddiqui HA, Calina D, Sharifi-Rad J, Cho WC. Interplay of oxidative stress, cellular communication and signaling pathways in cancer. Cell Commun Signal 2024; 22:7. [PMID: 38167159 PMCID: PMC10763046 DOI: 10.1186/s12964-023-01398-5] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 11/14/2023] [Indexed: 01/05/2024] Open
Abstract
Cancer remains a significant global public health concern, with increasing incidence and mortality rates worldwide. Oxidative stress, characterized by the production of reactive oxygen species (ROS) within cells, plays a critical role in the development of cancer by affecting genomic stability and signaling pathways within the cellular microenvironment. Elevated levels of ROS disrupt cellular homeostasis and contribute to the loss of normal cellular functions, which are associated with the initiation and progression of various types of cancer. In this review, we have focused on elucidating the downstream signaling pathways that are influenced by oxidative stress and contribute to carcinogenesis. These pathways include p53, Keap1-NRF2, RB1, p21, APC, tumor suppressor genes, and cell type transitions. Dysregulation of these pathways can lead to uncontrolled cell growth, impaired DNA repair mechanisms, and evasion of cell death, all of which are hallmark features of cancer development. Therapeutic strategies aimed at targeting oxidative stress have emerged as a critical area of investigation for molecular biologists. The objective is to limit the response time of various types of cancer, including liver, breast, prostate, ovarian, and lung cancers. By modulating the redox balance and restoring cellular homeostasis, it may be possible to mitigate the damaging effects of oxidative stress and enhance the efficacy of cancer treatments. The development of targeted therapies and interventions that specifically address the impact of oxidative stress on cancer initiation and progression holds great promise in improving patient outcomes. These approaches may include antioxidant-based treatments, redox-modulating agents, and interventions that restore normal cellular function and signaling pathways affected by oxidative stress. In summary, understanding the role of oxidative stress in carcinogenesis and targeting this process through therapeutic interventions are of utmost importance in combating various types of cancer. Further research is needed to unravel the complex mechanisms underlying oxidative stress-related pathways and to develop effective strategies that can be translated into clinical applications for the management and treatment of cancer. Video Abstract.
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Affiliation(s)
| | - Ayesha Kabeer
- Department of Biotechnology, University of Sialkot, Sialkot, Punjab, Pakistan
- Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Zaighum Abbas
- Department of Biotechnology, University of Sialkot, Sialkot, Punjab, Pakistan
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
| | | | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong.
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11
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Ray SK, Jayashankar E, Kotnis A, Mukherjee S. Oxidative versus Reductive Stress in Breast Cancer Development and Cellular Mechanism of Alleviation: A Current Perspective with Anti-breast Cancer Drug Resistance. Curr Mol Med 2024; 24:205-216. [PMID: 36892117 DOI: 10.2174/1566524023666230309112751] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 03/10/2023]
Abstract
Redox homeostasis is essential for keeping our bodies healthy, but it also helps breast cancer cells grow, stay alive, and resist treatment. Changes in the redox balance and problems with redox signaling can make breast cancer cells grow and spread and make them resistant to chemotherapy and radiation therapy. Reactive oxygen species/reactive nitrogen species (ROS/RNS) generation and the oxidant defense system are out of equilibrium, which causes oxidative stress. Many studies have shown that oxidative stress can affect the start and spread of cancer by interfering with redox (reduction-oxidation) signaling and damaging molecules. The oxidation of invariant cysteine residues in FNIP1 is reversed by reductive stress, which is brought on by protracted antioxidant signaling or mitochondrial inactivity. This permits CUL2FEM1B to recognize its intended target. After the proteasome breaks down FNIP1, mitochondrial function is restored to keep redox balance and cell integrity. Reductive stress is caused by unchecked amplification of antioxidant signaling, and changes in metabolic pathways are a big part of breast tumors' growth. Also, redox reactions make pathways like PI3K, PKC, and protein kinases of the MAPK cascade work better. Kinases and phosphatases control the phosphorylation status of transcription factors like APE1/Ref-1, HIF-1, AP-1, Nrf2, NF-B, p53, FOXO, STAT, and - catenin. Also, how well anti-breast cancer drugs, especially those that cause cytotoxicity by making ROS, treat patients depends on how well the elements that support a cell's redox environment work together. Even though chemotherapy aims to kill cancer cells, which it does by making ROS, this can lead to drug resistance in the long run. The development of novel therapeutic approaches for treating breast cancer will be facilitated by a better understanding of the reductive stress and metabolic pathways in tumor microenvironments.
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Affiliation(s)
- Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh, 462020, India
| | - Erukkambattu Jayashankar
- Department of Pathology & Lab Medicine, All India Institute of Medical Sciences-Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, 462020, India
| | - Ashwin Kotnis
- Department of Biochemistry, All India Institute of Medical Sciences-Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, 462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences-Bhopal, Saket Nagar, Bhopal, Madhya Pradesh, 462020, India
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12
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Peng Y, Liu QZ, Xu D, Fu JY, Zhang LX, Qiu L, Lin JG. M 4IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit colon cancer cells. Biochem Pharmacol 2023; 217:115856. [PMID: 37838274 DOI: 10.1016/j.bcp.2023.115856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/26/2023] [Accepted: 10/11/2023] [Indexed: 10/16/2023]
Abstract
Maintaining redox homeostasis is an essential feature of cancer cells, and disrupting this homeostasis to cause oxidative stress and induce cell death is an important strategy in cancer therapy. M4IDP, a zoledronic acid derivative, can cause the death of human colorectal cancer cells by increasing the level of intracellular reactive oxygen species (ROS). However, its potential molecular mechanism is unclear. Our in vitro studies showed that treatment with M4IDP promoted oxidative stress in HCT116 cells, as measured by the decreased ratios of GSH/GSSG and NADPH/NADP+ and increased level of MDA. M4IDP could cause the decrease of GSH content, the increase of GSSG content, the decrease of NADPH content and pentose phosphate pathway flux, the downregulation of G6PD expression, the upregulation of unprenylated Rap1A and total expression of RhoA and CDC42. The increase of ROS and cytotoxicity induced by M4IDP could be reversed by the supplementation of NADPH, the overexpression of G6PD and the supplementation of GGOH. In vivo studies showed that M4IDP inhibited tumor growth in the human colorectal cancer xenograft mouse model, which was accompanied with a decreased [18F]FDG uptake. Collectively, these results provide evidence that M4IDP can promote oxidation in colon cancer cells by inhibiting mevalonate pathway and pentose phosphate pathway and produce therapeutic effect. This study revealed for the first time a possible mechanism of bisphosphonate-induced increase of ROS in malignant tumor cells. This is helpful for the development of new molecular therapeutic targets and can provide new ideas for the combined therapy of bisphosphonates in tumors.
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Affiliation(s)
- Ying Peng
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Qing-Zhu Liu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China
| | - Dong Xu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China
| | - Jia-Yu Fu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Li-Xia Zhang
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China
| | - Ling Qiu
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jian-Guo Lin
- NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
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13
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Xia L, Ma W, Afrashteh A, Sajadi MA, Fakheri H, Valilo M. The nuclear factor erythroid 2-related factor 2/p53 axis in breast cancer. Biochem Med (Zagreb) 2023; 33:030504. [PMID: 37841775 PMCID: PMC10564154 DOI: 10.11613/bm.2023.030504] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023] Open
Abstract
One of the most important factors involved in the response to oxidative stress (OS) is the nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of components such as antioxidative stress proteins and enzymes. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1) keeps Nrf2 in the cytoplasm, thus preventing its translocation to the nucleus and inhibiting its role. It has been established that Nrf2 has a dual function; on the one hand, it promotes angiogenesis and cancer cell metastasis while causing resistance to drugs and chemotherapy. On the other hand, Nrf2 increases expression and proliferation of glutathione to protect cells against OS. p53 is a tumour suppressor that activates the apoptosis pathway in aging and cancer cells in addition to stimulating the glutaminolysis and antioxidant pathways. Cancer cells use the antioxidant ability of p53 against OS. Therefore, in the present study, we discussed function of Nrf2 and p53 in breast cancer (BC) cells to elucidate their role in protection or destruction of cancer cells as well as their drug resistance or antioxidant properties.
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Affiliation(s)
- Lei Xia
- Surgical oncology ward 2, Qinghai Provincial People’s Hospital, Xining Qinghai, China
| | - Wenbiao Ma
- Surgical oncology ward 2, Qinghai Provincial People’s Hospital, Xining Qinghai, China
| | - Ahmad Afrashteh
- Department of Periodontics, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Hadi Fakheri
- Paramedical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Valilo
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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14
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 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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15
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Didier AJ, Stiene J, Fang L, Watkins D, Dworkin LD, Creeden JF. Antioxidant and Anti-Tumor Effects of Dietary Vitamins A, C, and E. Antioxidants (Basel) 2023; 12:632. [PMID: 36978880 PMCID: PMC10045152 DOI: 10.3390/antiox12030632] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/20/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Oxidative stress, a condition characterized by an imbalance between pro-oxidant molecules and antioxidant defense systems, is increasingly recognized as a key contributor to cancer development. This is because the reactive oxygen species (ROS) generated during oxidative stress can damage DNA, proteins, and lipids to facilitate mutations and other cellular changes that promote cancer growth. Antioxidant supplementation is a potential strategy for decreasing cancer incidence; by reducing oxidative stress, DNA damage and other deleterious cellular changes may be attenuated. Several clinical trials have been conducted to investigate the role of antioxidant supplements in cancer prevention. Some studies have found that antioxidant supplements, such as vitamin A, vitamin C, and vitamin E, can reduce the risk of certain types of cancer. On the other hand, some studies posit an increased risk of cancer with antioxidant supplement use. In this review, we will provide an overview of the current understanding of the role of oxidative stress in cancer formation, as well as the potential benefits of antioxidant supplementation in cancer prevention. Additionally, we will discuss both preclinical and clinical studies highlighting the potentials and limitations of preventive antioxidant strategies.
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Affiliation(s)
- Alexander J. Didier
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
| | | | | | | | | | - Justin F. Creeden
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
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16
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Khan SU, Fatima K, Aisha S, Hamza B, Malik F. Redox balance and autophagy regulation in cancer progression and their therapeutic perspective. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:12. [PMID: 36352310 DOI: 10.1007/s12032-022-01871-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/30/2022] [Indexed: 11/10/2022]
Abstract
Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies.
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Affiliation(s)
- Sameer Ullah Khan
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India.
| | - Kaneez Fatima
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India
| | - Shariqa Aisha
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
| | - Baseerat Hamza
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India
| | - Fayaz Malik
- Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar, 190005, Jammu and Kashmir, India.
- Academy of Scientific and Innovative Research (AcSIR), Sanat Nagar, Ghaziabad, 201002, India.
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17
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Nrf2 Modulation in Breast Cancer. Biomedicines 2022; 10:biomedicines10102668. [PMID: 36289931 PMCID: PMC9599257 DOI: 10.3390/biomedicines10102668] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/05/2022] [Accepted: 10/19/2022] [Indexed: 12/05/2022] Open
Abstract
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.
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18
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Liu X, Liu H, Zeng L, Lv Y. BRCA1 overexpression attenuates breast cancer cell growth and migration by regulating the pyruvate kinase M2-mediated Warburg effect via the PI3K/AKT signaling pathway. PeerJ 2022; 10:e14052. [PMID: 36193432 PMCID: PMC9526413 DOI: 10.7717/peerj.14052] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/23/2022] [Indexed: 01/19/2023] Open
Abstract
This work explored the mechanism of the effect of breast-cancer susceptibility gene 1 (BRCA1) on the metabolic characteristics of breast cancer cells, including the Warburg effect and its specific signaling. We transfected MCF-7 cells with a BRCA1-encoding LXSN plasmid or PKM2 siRNA and examined cancer cell metabolism using annexin V staining, inhibitory concentration determination, Western blotting, glucose uptake and lactic acid content measurements, and Transwell assays to assess glycolytic activity, cell apoptosis, and migration, and sensitivity to anti-cancer treatment. The BRCA1-expressing MCF-7 cells demonstrated low PKM2 expression and decreased glycolytic activity (downregulated hexokinase 2 (HK2) expression, upregulated isocitrate dehydrogenase 1 (IDH1) expression, and reduced O2 and glucose consumption and lactate production) via regulation of PI3K/AKT pathway compared with the empty LXSN group. BRCA1 transfection slightly increased apoptotic activity, decreased cell migration, and increased the IC50 index for doxorubicin, paclitaxel, and cisplatin. Inhibiting PKM2 using siRNA attenuated the IC50 index for doxorubicin, paclitaxel, and cisplatin compared with the control. Inhibiting PKM2 activated PI3K/AKT signaling, increased apoptosis, and decreased MCF-7 cell migration. Our data suggest that BRCA1 overexpression reverses the Warburg effect, inhibits cancer cell growth and migration, and enhances the sensitivity to anti-cancer treatment by decreasing PKM2 expression regulated by PI3K/AKT signaling. These novel metabolic findings represent a potential mechanism by which BRCA1 exerts its inhibitory effect on breast cancer.
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White JA, Kaninjing ET, Adeniji KA, Jibrin P, Obafunwa JO, Ogo CN, Mohammed F, Popoola A, Fatiregun OA, Oluwole OP, Karanam B, Elhussin I, Ambs S, Tang W, Davis M, Polak P, Campbell MJ, Brignole KR, Rotimi SO, Dean-Colomb W, Odedina FT, Martin DN, Yates C. Whole-exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry. CANCER RESEARCH COMMUNICATIONS 2022; 2:1005-1016. [PMID: 36922933 PMCID: PMC10010347 DOI: 10.1158/2767-9764.crc-22-0136] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/23/2022] [Accepted: 08/08/2022] [Indexed: 12/30/2022]
Abstract
In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naïve Nigerian (NG) primary prostate cancer tumors and 11 unmatched nontumor tissues to compare genomic mutations with African American (AA) and European American (EA) The Cancer Genome Atlas (TCGA) prostate cancer. NG samples were collected from six sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG nontumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (P ≤ 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene-level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African ancestry increased. BRCA2_rs11571831 was present only in MAA, and BRCA2_rs766173 was elevated in NG men. A total of 133 somatic variants were present in 26 prostate cancer-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies >10%. Compared with TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities ≥0.734) with Catalogue of Somatic Mutations in Cancer signatures 5 and 6, and mutated genes showed significant (q < 0.001) gene ontology (GO) and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that mutations in DNA damage response genes were higher in NG prostate cancer samples and that a portion of those mutations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG prostate cancer exome to date and highlight the need to increase diversity of study populations. Significance MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.
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Affiliation(s)
- Jason A White
- Tuskegee University, Center for Cancer Research, Tuskegee, Alabama
| | | | | | | | - John O Obafunwa
- Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
| | | | | | | | | | | | | | - Isra Elhussin
- Tuskegee University, Center for Cancer Research, Tuskegee, Alabama
| | - Stefan Ambs
- Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Wei Tang
- Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland
| | - Melissa Davis
- Department of Surgery, New York Presbyterian - Weill Cornell Medicine, New York, New York
| | | | - Moray J Campbell
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | | | | | - Windy Dean-Colomb
- Tuskegee University, Center for Cancer Research, Tuskegee, Alabama.,Piedmont Medical Oncology - Newnan, Newnan, Georgia
| | - Folake T Odedina
- Center for Health Equity and Community Engagement Research, Mayo Clinic, Jacksonville, Florida
| | - Damali N Martin
- Division of Cancer Control and Population Sciences, NCI, Rockville, Maryland
| | - Clayton Yates
- Tuskegee University, Center for Cancer Research, Tuskegee, Alabama
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20
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Yegiazaryan A, Abnousian A, Alexander LJ, Badaoui A, Flaig B, Sheren N, Aghazarian A, Alsaigh D, Amin A, Mundra A, Nazaryan A, Guilford FT, Venketaraman V. Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19. Int J Mol Sci 2022; 23:9297. [PMID: 36012562 PMCID: PMC9409103 DOI: 10.3390/ijms23169297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 08/16/2022] [Accepted: 08/16/2022] [Indexed: 02/03/2023] Open
Abstract
Coronaviruses represent a diverse family of enveloped positive-sense single stranded RNA viruses. COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus-2, is a highly contagious respiratory disease transmissible mainly via close contact and respiratory droplets which can result in severe, life-threatening respiratory pathologies. It is understood that glutathione, a naturally occurring antioxidant known for its role in immune response and cellular detoxification, is the target of various proinflammatory cytokines and transcription factors resulting in the infection, replication, and production of reactive oxygen species. This leads to more severe symptoms of COVID-19 and increased susceptibility to other illnesses such as tuberculosis. The emergence of vaccines against COVID-19, usage of monoclonal antibodies as treatments for infection, and implementation of pharmaceutical drugs have been effective methods for preventing and treating symptoms. However, with the mutating nature of the virus, other treatment modalities have been in research. With its role in antiviral defense and immune response, glutathione has been heavily explored in regard to COVID-19. Glutathione has demonstrated protective effects on inflammation and downregulation of reactive oxygen species, thereby resulting in less severe symptoms of COVID-19 infection and warranting the discussion of glutathione as a treatment mechanism.
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Affiliation(s)
- Aram Yegiazaryan
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Arbi Abnousian
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Logan J. Alexander
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Ali Badaoui
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Brandon Flaig
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Nisar Sheren
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Armin Aghazarian
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Dijla Alsaigh
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Arman Amin
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Akaash Mundra
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Anthony Nazaryan
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | | | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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21
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Giudice A, Aliberti SM, Barbieri A, Pentangelo P, Bisogno I, D'Arena G, Cianciola E, Caraglia M, Capunzo M. Potential Mechanisms by which Glucocorticoids Induce Breast Carcinogenesis through Nrf2 Inhibition. FRONT BIOSCI-LANDMRK 2022; 27:223. [PMID: 35866405 DOI: 10.31083/j.fbl2707223] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 01/03/2025]
Abstract
Breast cancer is the most common malignancy among women worldwide. Several studies indicate that, in addition to established risk factors for breast cancer, other factors such as cortisol release related to psychological stress and drug treatment with high levels of glucocorticoids may also contribute significantly to the initiation of breast cancer. There are several possible mechanisms by which glucocorticoids might promote neoplastic transformation of breast tissue. Among these, the least known and studied is the inhibition of the nuclear erythroid factor 2-related (Nrf2)-antioxidant/electrophile response element (ARE/EpRE) pathway by high levels of glucocorticoids. Specifically, Nrf2 is a potent transcriptional activator that plays a central role in the basal and inducible expression of many cytoprotective genes that effectively protect mammalian cells from various forms of stress and reduce the propensity of tissues and organisms to develop disease or malignancy including breast cancer. Consequently, a loss of Nrf2 in response to high levels of gluco-corticoids may lead to a decrease in cellular defense against oxidative stress, which plays an important role in the initiation of human mammary carcinogenesis. In the present review, we provide a comprehensive overview of the current state of knowledge of the cellular mechanisms by which both glucocorticoid pharmacotherapy and endogenous GCs (cortisol in humans and corticosterone in rodents) may contribute to breast cancer development through inhibition of the Nrf2-ARE/EpRE pathway and the protective role of melatonin against glucocorticoid-induced apoptosis in the immune system.
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Affiliation(s)
- Aldo Giudice
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Silvana Mirella Aliberti
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Paola Pentangelo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Ilaria Bisogno
- Department of Radiological, Oncological and Anatomo-Pathological Science, University of Rome "Sapienza", 00161 Rome, Italy
| | - Giovanni D'Arena
- Hematology Service, San Luca Hospital, ASL Salerno, 84124 Salerno, Italy
| | - Emidio Cianciola
- Anesthesia and Intensive Care Unit, "Immacolata di Sapri" Hospital- ASL Salerno, 84073 Salerno, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
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22
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Alizadeh S, Anani-Sarab G, Amiri H, Hashemi M. Paraquat induced oxidative stress, DNA damage, and cytotoxicity in lymphocytes. Heliyon 2022; 8:e09895. [PMID: 35855999 PMCID: PMC9287805 DOI: 10.1016/j.heliyon.2022.e09895] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 04/26/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Paraquat (PQ) is a herbicide belonging to the group of bipyridylium salts. The objective of this study was to evaluate oxidative stress, DNA damage, and cytotoxicity induced by paraquat in peripheral lymphocyte cells in vivo as well as pathological changes in various tissues. For this purpose, 28 male Wistar rats in 6 different groups were poisoned by paraquat gavage and blood samples were taken from the hearts of rats after during the poisoning period. Oxidative stress, DNA damage, cell membrane integrity, serum lactate dehydrogenase, and cytotoxicity, were investigated by Ferric Reducing Antioxidant Potential (FRAP) test, alkaline comet assay, measuring serum lactate dehydrogenase (LDH), Hoechst staining and flow cytometry with propidium iodide (PI) respectively. The lung, kidney, and liver tissues were also examined pathologically. Paraquat caused dose-dependent DNA damage in peripheral lymphocyte cells and significant oxidative cell membrane damage. The most damage was caused by a single dose of 200 mg/kg b.w of paraquat by gavage. The gradual exposure to a dose of 300 mg/kg b.w of paraquat showed less damage, which could be due to the activation of the antioxidant defense mechanism.
Paraquat induced oxidative stress. Paraquat increases serum lactate dehydrogenase. Oxidative stress Inducted by exposure to paraquat Inducted DNA damage.
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Affiliation(s)
- Soheila Alizadeh
- Environmental Health Engineering Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Department of Environmental Health Engineering, Faculty of Public Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Gholamreza Anani-Sarab
- Medical Toxicology & Drug Abuse Research Center Birjand University of Medical Sciences, Birjand, Iran.,School of Allied Medical Sciences Birjand University of Medical Sciences, Birjand, Iran
| | - Hoda Amiri
- Environmental Health Engineering Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Department of Environmental Health Engineering, Faculty of Public Health, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Hashemi
- Environmental Health Engineering Research Center, Kerman University of Medical Sciences, Kerman, Iran.,Department of Environmental Health Engineering, Faculty of Public Health, Kerman University of Medical Sciences, Kerman, Iran.,Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
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23
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Oncogenic Kras-Mediated Cytokine CCL15 Regulates Pancreatic Cancer Cell Migration and Invasion through ROS. Cancers (Basel) 2022; 14:cancers14092153. [PMID: 35565279 PMCID: PMC9104113 DOI: 10.3390/cancers14092153] [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: 03/25/2022] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Oncogenic KrasG12D and tumor inflammation are critical components of the development and dissemination of pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to investigate a lesser-known cytokine, CCL15, that functions as a new downstream target of KrasG12D with the purpose of regulating PDAC cell migration and invasion. We showed increased levels of CCL15 as well as the presence of its receptors, including CCR1 and CCR3, in PDAC tissues and cell lines. The knockdown of CCL15 diminished metastatic Panc-1 cell migration, whereas the treatment of CCL15 in non-metastatic BxPC-3 cells promoted BxPC-3 cell motility. Similar results were verified using murine metastatic PDAC KP-2 cells. Furthermore, we demonstrated that CCL15-modulated PDAC cell migration through the upregulation of cellular reactive oxygen species (ROS) levels and the knockdown of KrasG12D resulted in a decrease in CCL15. Altogether, our data unveiled a new mechanism of oncogenic KrasG12D in modulating PDAC inflammation and spreading. Abstract Pancreatic ductal adenocarcinoma (PDAC) is well known for its high death rate due to prompt cancer metastasis caused by cancer cell migration and invasion within the early stages of its development. Here, we reveal a new function of cytokine CCL15, namely the upregulation of PDAC cell migration and invasion. We showed increased levels of CCL15 transcripts and protein expressions in human PDAC tissue samples, as well as in cultured cell lines. Furthermore, PDAC cells also expressed CCL15 receptors, including CCR1 and CCR3. Murine PDAC cell lines and tissues strengthened this finding. The manipulation of CCL15 in metastatic Panc-1 cells through CCL15 knockdown or CCL15 neutralization decreased Panc-1 cell motility and invasiveness. In addition, treating non-metastatic BxPC-3 cells with recombinant CCL15 accelerated the cell migration of BxPC-3. A reduction in the levels of reactive oxygen species (ROS) by either N-Acetyl-L-Cysteine treatment or p22phox knockdown led to a decrease in Panc-1 cell migration and a reversed effect on recombinant CCL15-promoted BxPC-3 cell movement. Importantly, the knockdown of oncogenic Kras in Panc-1 cells abolished CCL15 protein expression and impeded cell migration without affecting PDAC cell growth. Altogether, our work elucidates an additional molecular pathway of oncogenic Kras to promote PDAC metastasis through the upregulation of cell migration and invasion by the Kras downstream CCL15, a lesser-known cytokine within the cancer research field.
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24
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Xi X, Wang J, Qin Y, You Y, Huang W, Zhan J. The Biphasic Effect of Flavonoids on Oxidative Stress and Cell Proliferation in Breast Cancer Cells. Antioxidants (Basel) 2022; 11:antiox11040622. [PMID: 35453307 PMCID: PMC9032920 DOI: 10.3390/antiox11040622] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/15/2022] [Accepted: 03/23/2022] [Indexed: 12/21/2022] Open
Abstract
Flavonoids have been reported to play an essential role in modulating processes of cellular redox homeostasis such as scavenging ROS. Meanwhile, they also induce oxidative stress that exerts potent antitumor bioactivity. However, the contradiction between these two aspects still remains unclear. In this study, four typical flavonoids were selected and studied. The results showed that low-dose flavonoids slightly promoted the proliferation of breast cancer cells under normal growth via gradually reducing accumulated oxidative products and demonstrated a synergistic effect with reductants NAC or VC. Besides, low-dose flavonoids significantly reduced the content of ROS and MDA induced by LPS or Rosup but restored the activity of SOD. However, high-dose flavonoids markedly triggered the cell death via oxidative stress as evidenced by upregulated ROS, MDA and downregulated SOD activity that could be partly rescued by NAC pretreatment, which was also confirmed by antioxidative gene expression levels. The underlying mechanism of such induced cell death was pinpointed as apoptosis, cell cycle arrest, accumulated mitochondrial superoxide, impaired mitochondrial function and decreased ATP synthesis. Transcriptomic analysis of apigenin and quercetin uncovered that high-dose flavonoids activated TNF-α signaling, as verified through detecting inflammatory gene levels in breast cancer cells and RAW 264.7 macrophages. Moreover, we identified that BRCA1 overexpression effectively attenuated such oxidative stress, inflammation and inhibited ATP synthesis induced by LPS or high dose of flavonoids possibly through repairing DNA damage, revealing an indispensable biological function of BRCA1 in resisting oxidative damage and inflammatory stimulation caused by exogenous factors.
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25
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Gall Trošelj K, Tomljanović M, Jaganjac M, Matijević Glavan T, Čipak Gašparović A, Milković L, Borović Šunjić S, Buttari B, Profumo E, Saha S, Saso L, Žarković N. Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response. Molecules 2022; 27:1468. [PMID: 35268568 PMCID: PMC8912061 DOI: 10.3390/molecules27051468] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/11/2022] [Accepted: 02/19/2022] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of Antioxidant Response Element (ARE)-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.
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Affiliation(s)
- Koraljka Gall Trošelj
- Laboratory for Epigenomics, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia;
| | - Marko Tomljanović
- Laboratory for Epigenomics, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia;
| | - Morana Jaganjac
- Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia; (M.J.); (A.Č.G.); (L.M.); (S.B.Š.); (N.Ž.)
| | - Tanja Matijević Glavan
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia;
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia; (M.J.); (A.Č.G.); (L.M.); (S.B.Š.); (N.Ž.)
| | - Lidija Milković
- Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia; (M.J.); (A.Č.G.); (L.M.); (S.B.Š.); (N.Ž.)
| | - Suzana Borović Šunjić
- Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia; (M.J.); (A.Č.G.); (L.M.); (S.B.Š.); (N.Ž.)
| | - Brigitta Buttari
- Department of Cardiovascular, Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy; (B.B.); (E.P.); (S.S.)
| | - Elisabetta Profumo
- Department of Cardiovascular, Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy; (B.B.); (E.P.); (S.S.)
| | - Sarmistha Saha
- Department of Cardiovascular, Endocrine-Metabolic Diseases, and Aging, Italian National Institute of Health, 00161 Rome, Italy; (B.B.); (E.P.); (S.S.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00161 Rome, Italy;
| | - Neven Žarković
- Laboratory for Oxidative Stress (LabOS), Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia; (M.J.); (A.Č.G.); (L.M.); (S.B.Š.); (N.Ž.)
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26
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Kobayashi H, Imanaka S, Shigetomi H. Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis. Oncol Lett 2022; 23:80. [PMID: 35111249 PMCID: PMC8771630 DOI: 10.3892/ol.2022.13200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Recent advances in molecular genetics have expanded our understanding of ovarian cancer. High levels of reactive oxygen species (ROS) and upregulation of antioxidant genes are common characteristic features of human cancers. This review reconsiders novel therapeutic strategies for ovarian cancer by focusing on redox homeostasis. A literature search was performed for preclinical and clinical studies published between January 1998 and October 2021 in the PubMed database using a combination of specific terms. ROS serves a central role in tumor suppression and progression by inducing DNA damage and mutations, genomic instability, and aberrant anti- and pro-tumorigenic signaling. Cancer cells increase their antioxidant capacity to neutralize the extra ROS. Additionally, antioxidants, such as CD44 variant isoform 9 (CD44v9) and nuclear factor erythroid 2-related factor 2 (Nrf2), mediate redox homeostasis in ovarian cancer. Furthermore, studies conducted on different cancer types revealed the dual role of antioxidants in tumor progression and inhibition. However, in animal models, genetic loss of antioxidant capacity in the host cannot block cancer initiation and progression. Host-derived antioxidant systems are essential to suppress carcinogenesis, suggesting that antioxidants serve a pivotal role in suppressing cancer development. By contrast, antioxidant activation in cancer cells confers aggressive phenotypes. Antioxidant inhibitors can promote cancer cell death by enhancing ROS levels. Concurrent inhibition of CD44v9 and Nrf2 may trigger apoptosis induction, potentiate chemosensitivity and enhance antitumor activities through the ROS-activated p38/p21 pathway. Antioxidants may have tumor-promoting and -suppressive functions. Therefore, an improved understanding of the role of antioxidants in redox homeostasis and developing antioxidant-specific inhibitors is necessary for treating ovarian cancer.
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Affiliation(s)
- Hiroshi Kobayashi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Shogo Imanaka
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Ms. Clinic MayOne, Kashihara, Nara 634-0813, Japan
| | - Hiroshi Shigetomi
- Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.,Department of Obstetrics and Gynecology, Aska Ladies Clinic, Nara 634-0001, Japan
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27
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Russi M, Marson D, Fermeglia A, Aulic S, Fermeglia M, Laurini E, Pricl S. The fellowship of the RING: BRCA1, its partner BARD1 and their liaison in DNA repair and cancer. Pharmacol Ther 2021; 232:108009. [PMID: 34619284 DOI: 10.1016/j.pharmthera.2021.108009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 08/22/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022]
Abstract
The breast cancer type 1 susceptibility protein (BRCA1) and its partner - the BRCA1-associated RING domain protein 1 (BARD1) - are key players in a plethora of fundamental biological functions including, among others, DNA repair, replication fork protection, cell cycle progression, telomere maintenance, chromatin remodeling, apoptosis and tumor suppression. However, mutations in their encoding genes transform them into dangerous threats, and substantially increase the risk of developing cancer and other malignancies during the lifetime of the affected individuals. Understanding how BRCA1 and BARD1 perform their biological activities therefore not only provides a powerful mean to prevent such fatal occurrences but can also pave the way to the development of new targeted therapeutics. Thus, through this review work we aim at presenting the major efforts focused on the functional characterization and structural insights of BRCA1 and BARD1, per se and in combination with all their principal mediators and regulators, and on the multifaceted roles these proteins play in the maintenance of human genome integrity.
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Affiliation(s)
- Maria Russi
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Domenico Marson
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Alice Fermeglia
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Suzana Aulic
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Maurizio Fermeglia
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Erik Laurini
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy
| | - Sabrina Pricl
- Molecular Biology and Nanotechnology Laboratory (MolBNL@UniTs), DEA, University of Trieste, Trieste, Italy; Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland.
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28
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Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression. Pharmacol Ther 2021; 232:107992. [PMID: 34606782 DOI: 10.1016/j.pharmthera.2021.107992] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 09/02/2021] [Accepted: 09/07/2021] [Indexed: 02/08/2023]
Abstract
Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.
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29
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Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation. Cancers (Basel) 2021; 13:cancers13194818. [PMID: 34638302 PMCID: PMC8508278 DOI: 10.3390/cancers13194818] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) are a tumor cell population maintaining tumor growth and promoting tumor relapse if not wholly eradicated during treatment. CSCs are often equipped with molecular mechanisms making them resistant to conventional anti-cancer therapies whose curative potential depends on DNA damage-induced cell death. An elevated expression of some key DNA repair proteins is one of such defense mechanisms. However, new research reveals that the role of critical DNA repair proteins is extending far beyond the DNA repair mechanisms. This review discusses the diverse biological functions of DNA repair proteins in CSC maintenance and the adaptation to replication and oxidative stress, anti-cancer immune response, epigenetic reprogramming, and intracellular signaling mechanisms. It also provides an overview of their potential therapeutic targeting. Abstract Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets.
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30
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Marchal L, Hamsanathan S, Karthikappallil R, Han S, Shinglot H, Gurkar AU. Analysis of representative mutants for key DNA repair pathways on healthspan in Caenorhabditis elegans. Mech Ageing Dev 2021; 200:111573. [PMID: 34562508 DOI: 10.1016/j.mad.2021.111573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 08/26/2021] [Accepted: 09/21/2021] [Indexed: 12/30/2022]
Abstract
Although the link between DNA damage and aging is well accepted, the role of different DNA repair proteins on functional/physiological aging is not well-defined. Here, using Caenorhabditis elegans, we systematically examined the effect of three DNA repair genes involved in key genome stability pathways. We assayed multiple health proxies including molecular, functional and resilience measures to define healthspan. Loss of XPF-1/ERCC-1, a protein involved in nucleotide excision repair (NER), homologous recombination (HR) and interstrand crosslink (ICL) repair, showed the highest impairment of functional and stress resilience measures along with a shortened lifespan. brc-1 mutants, with a well-defined role in HR and ICL are short-lived and highly sensitive to acute stressors, specifically oxidative stress. In contrast, ICL mutant, fcd-2 did not impact lifespan or most healthspan measures. Our efforts also uncover that DNA repair mutants show high sensitivity to oxidative stress with age, suggesting that this measure could act as a primary proxy for healthspan. Together, these data suggest that impairment of multiple DNA repair genes can drive functional/physiological aging. Further studies to examine specific DNA repair genes in a tissue specific manner will help dissect the importance and mechanistic role of these repair systems in biological aging.
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Affiliation(s)
- Lucile Marchal
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA
| | - Shruthi Hamsanathan
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA
| | - Roshan Karthikappallil
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA; Medical Sciences Division, University of Oxford, Oxford, UK
| | - Suhao Han
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA
| | - Himaly Shinglot
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA
| | - Aditi U Gurkar
- Aging Institute of UPMC and the University of Pittsburgh School of Medicine, 100 Technology Dr, Pittsburgh, PA, 15219, USA; Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Kaufmann Medical Building Suite 500, Pittsburgh, PA, 15213, USA; Geriatric Research, Education and Clinical Centre, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, 15240, USA.
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31
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Shah MA, Rogoff HA. Implications of reactive oxygen species on cancer formation and its treatment. Semin Oncol 2021; 48:238-245. [PMID: 34548190 DOI: 10.1053/j.seminoncol.2021.05.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/17/2020] [Accepted: 05/26/2021] [Indexed: 12/23/2022]
Abstract
Elevated levels of reactive oxygen species (ROS) are a hallmark of cancer. Although increased ROS concentrations play important roles in cancer formation and progression, levels above a cytotoxic threshold cause cancer cell death. Cancer cells adapt to high concentrations of ROS via antioxidant production and reprogrammed cellular metabolism (eg, the Warburg effect). Because some widely used anticancer therapies such as radiation therapy and chemotherapy rely on ROS accumulation as a mechanism to induce cancer cell death, a cancer cell's ability to control ROS levels is a driver of treatment resistance and a critical consideration for successful cancer treatment. The necessity for cancer cells to adapt to elevated levels of ROS to survive may represent an Achilles heel for some malignancies, as therapies designed to interfere with this adaptation would be expected to kill cancer cells. In this review, we provide an overview of the implications of ROS on cancer formation and anticancer treatment strategies, with a focus on treatment-resistant disease.
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Affiliation(s)
- Manish A Shah
- Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY, USA.
| | - Harry A Rogoff
- Sumitomo Dainippon Pharma Oncology, Inc., Cambridge, MA, USA
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Renaudin X, Lee M, Shehata M, Surmann EM, Venkitaraman AR. BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance. Cell Rep 2021; 36:109478. [PMID: 34348152 PMCID: PMC8356021 DOI: 10.1016/j.celrep.2021.109478] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 06/16/2021] [Accepted: 07/13/2021] [Indexed: 01/07/2023] Open
Abstract
Oxidative stress is a ubiquitous cellular challenge implicated in aging, neurodegeneration, and cancer. By studying pathogenic mutations in the tumor suppressor BRCA2, we identify a general mechanism by which oxidative stress restricts mitochondrial (mt)DNA replication. BRCA2 inactivation induces R-loop accumulation in the mtDNA regulatory region and diminishes mtDNA replication initiation. In BRCA2-deficient cells, intracellular reactive oxygen species (ROS) are elevated, and ROS scavengers suppress the mtDNA defects. Conversely, wild-type cells exposed to oxidative stress by pharmacologic or genetic manipulation phenocopy these defects. Mechanistically, we find that 8-oxoguanine accumulation in mtDNA caused by oxidative stress suffices to impair recruitment of the mitochondrial enzyme RNaseH1 to sites of R-loop accrual, restricting mtDNA replication initiation. Thus, oxidative stress impairs RNaseH1 function to cripple mtDNA maintenance. Our findings highlight a molecular mechanism that links oxidative stress to mitochondrial dysfunction and is elicited by the inactivation of genes implicated in neurodegeneration and cancer.
BRCA2-deficient cells accumulate mtDNA R-loops due to oxidative stress This stress creates 8-oxoguanine lesions impairing RNaseH1 recruitment to mtDNA RNaseH1 impairment triggers R-loop formation and restricts mtDNA replication Other sources of oxidative stress also cripple mtDNA maintenance via this mechanism
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Affiliation(s)
- Xavier Renaudin
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK
| | - Miyoung Lee
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK
| | - Mona Shehata
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK
| | - Eva-Maria Surmann
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK
| | - Ashok R Venkitaraman
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
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CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma. Oncogene 2021; 40:4368-4383. [PMID: 34103686 DOI: 10.1038/s41388-021-01855-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 05/12/2021] [Accepted: 05/21/2021] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) patients mostly suffer from poor survival outcomes. It is necessary to identify effective therapeutic targets to improve prognosis for HCC patients. Here, we report a new factor, CDCA2, in promoting HCC development. CDCA2 amplification is an independent risk factor for the recurrence and survival of HCC patients, which is positively correlated with elevated level of alpha-fetoprotein (AFP), high histological grade, large tumor size, advanced TNM stage, and poor prognosis for HCC patients. In HCC cells, CDCA2 promotes cell growth and inhibits apoptosis. Mechanistically, CDCA2's transcription is activated through the binding of E2F2/E2F8 with its promoter. CDCA2 depletion contributes to the suppression of cell proliferation and induction of apoptosis due to reactive oxygen species (ROS)-mediated stress, which can be reversed by antioxidants N-acetyl cysteine (NAC) and glutathione (GSH). Interestingly, we found that CDCA2 triggers the BRCA1-NRF2 cascade, which elevates antioxidant response and attenuates ROS levels. In response to oxidative stress, CDCA2 promotes BRCA1's chromatin relocalization to NRF2, activating NRF2-driven downstream signaling (HO-1, TXNRD1, and NQO1), which then protects HCC cells against oxidative damage. In conclusion, our results reveal that CDCA2 is a prognostic biomarker for HCC patients, and present the E2F2/E2F8-CDCA2-BRCA1-NRF2-ROS signaling axis that have implications for HCC therapeutics.
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Zheng J, Mao Z, Zhang J, Jiang L, Wang N. Paeonol Pretreatment Attenuates Anoxia-Reoxygenation Induced Injury in Cardiac Myocytes via a BRCA1 Dependent Pathway. Chem Pharm Bull (Tokyo) 2021; 68:1163-1169. [PMID: 33268648 DOI: 10.1248/cpb.c20-00524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Breast cancer type 1 sensitive protein (BRCA1) is a well-known tumor suppressor and its role in oxidative stress has been confirmed. The purpose of this study is to evaluate whether paeonol has a protective effect on myocardial hypoxia-reoxygenation (A/R) injury, and to explore H9C2 cells through a mechanism-dependent pathway mediated by BRCA1. H9C2 cells were pretreated with paeonol (10 µM) for 18 h before hypoxia was induced to establish a cell model of myocardial ischemia/reperfusion (I/R) injury. Use commercial kits to detect antioxidant indicators, including relative oxygen content (ROS) levels, total antioxidant capacity (T-AOC), superoxide dismutase (SOD), lactate dehydrogenase (LDH) activity, and creatine kinase (CK-MB) and nuclear factor-kappaB (NF-κB) activity. The cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction method. Real-time fluorescent quantitative PCR was used to detect BRCA1 mRNA and protein levels. The expression levels of BRCA1, NLRP3 and ACS were determined by Western blotting. In addition, the release of interleukin (IL)-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) was also evaluated by an enzyme-linked immunosorbent assay (ELISA) kit. The results showed that paeonol (10 µM) can significantly improve the hypoxic A/R damage of H9C2 cells, and the BRCA1 expression of H9C2 cells pretreated with paeonol was significantly increased before A/R damage was induced. BRCA1 is widely known in breast and ovarian cancer. Our data proves that the down-regulation of BRCA1 participates in the decrease of cell viability and the decrease of CK-MB and LDH activities, and protects cells by inhibiting the production of ROS and the activation of Nod-like receptor protein 3 (NLRP3) inflammasomes and NF-κB. In conclusion, paeonol significantly improved the A/R damage of H9C2 cells induced by hypoxia through the BRCA1/ROS-regulated NLRP3 inflammasome/IL-1β and NF-κB/TNF-α/IL-6 pathways. It may be a potential drug against myocardial I/R injury.
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Affiliation(s)
- Jifeng Zheng
- Department of Cardiology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People's Hospital.,Department of Cardiology, The Affiliated Second Hospital of Jiaxing Medical University
| | - Zhiyao Mao
- Department of Cardiology, The Affiliated Second Hospital of Jiaxing Medical University
| | - Jianqin Zhang
- Department of Cardiology, The Affiliated Second Hospital of Jiaxing Medical University
| | - Liqing Jiang
- Department of Cardiology, The Affiliated Second Hospital of Jiaxing Medical University
| | - Ningfu Wang
- Department of Cardiology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou First People's Hospital
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Leung E, Hazrati LN. Breast cancer type 1 and neurodegeneration: consequences of deficient DNA repair. Brain Commun 2021; 3:fcab117. [PMID: 34222870 PMCID: PMC8242133 DOI: 10.1093/braincomms/fcab117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 12/20/2022] Open
Abstract
Numerous cellular processes, including toxic protein aggregation and oxidative stress, have been studied extensively as potential mechanisms underlying neurodegeneration. However, limited therapeutic efficacy targeting these processes has prompted other mechanisms to be explored. Previous research has emphasized a link between cellular senescence and neurodegeneration, where senescence induced by excess DNA damage and deficient DNA repair results in structural and functional changes that ultimately contribute to brain dysfunction and increased vulnerability for neurodegeneration. Specific DNA repair proteins, such as breast cancer type 1, have been associated with both stress-induced senescence and neurodegenerative diseases, however, specific mechanisms remain unclear. Therefore, this review explores DNA damage-induced senescence in the brain as a driver of neurodegeneration, with particular focus on breast cancer type 1, and its potential contribution to sex-specific differences associated with neurodegenerative disease.
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Affiliation(s)
- Emily Leung
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 Kings College Cir, Toronto, ON M5S 1A8, Canada
- The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada
| | - Lili-Naz Hazrati
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 Kings College Cir, Toronto, ON M5S 1A8, Canada
- The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada
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Guha S, Roy S. Enhanced expression of SLC4A11 by tert-Butylhydroquinone is mediated by direct binding of Nrf2 to the promoter of SLC4A11. Free Radic Biol Med 2021; 167:299-306. [PMID: 33744340 DOI: 10.1016/j.freeradbiomed.2021.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND SLC4A11, a Na + dependent OH- transporter, is highly expressed in the epithelium and endothelium of the cornea. Mutations in SLC4A11 cause congenital hereditary endothelial dystrophy (CHED), a progressive disease with gradual loss of vision and characterized by degeneration and dysfunction of corneal endothelial cells. SLC4A11 expression is also responsive to oxidative stress. Thus, understanding of SLC4A11 gene regulation is of utmost importance for therapeutic interventions. However, it remains elusive how SLC4A11 is regulated at transcriptional and translational level. METHODS Bioinformatics analysis of the SLC4A11 promoter was performed using TRANSFAC. SLC4A11 promoter constructs were generated and exposed to tert-Butylhydroquinone (tBHQ) or cotransfected with Nuclear factor erythroid 2-related factor 2 (Nrf2) expression plasmid and promoter activity was determined. The expression of SLC4A11 was also determined by quantitative PCR and immunoblot analysis. The binding of Nrf2 to the promoter of SLC4A11 was validated by chromatin immunoprecipitation assay. RESULTS Induction of Nrf2 by tBHQ or overexpression of Nrf2 caused increased expression of SLC4A11 in HeLa and human corneal endothelial cells. A conserved Nrf2 binding sequence was found in the promoter of SLC4A11 of several mammalian species. Reporter gene assays showed transcriptional activation of the SLC4A11 promoter in response to tBHQ treatment and Nrf2 overexpression. ChIP analysis validated Nrf2 binding to the conserved sequence of the SLC4A11 promoter. Induction of the Nrf2 pathway also resulted in increased endogenous SLC4A11 protein abundance. On the other hand, depletion of Nrf2 inhibited both transcriptional and translational activities of SLC4A11. CONCLUSION In summary, we determined direct Nrf2 binding to antioxidant responsive element site within the SLC4A11 promoter, and observed increased expression of SLC4A11 by Nrf2 inducers. To the best of our knowledge, this is the first study showing Nrf2 exerts an important role in regulation of SLC4A11 gene expression.
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Affiliation(s)
- Sanjukta Guha
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India; Manipal Academy of Higher Education, Manipal, India
| | - Sanhita Roy
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India.
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Huo Y, Selenica P, Mahdi AH, Pareja F, Kyker-Snowman K, Chen Y, Kumar R, Da Cruz Paula A, Basili T, Brown DN, Pei X, Riaz N, Tan Y, Huang YX, Li T, Barnard NJ, Reis-Filho JS, Weigelt B, Xia B. Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development. NPJ Breast Cancer 2021; 7:45. [PMID: 33893322 PMCID: PMC8065161 DOI: 10.1038/s41523-021-00253-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 03/24/2021] [Indexed: 02/08/2023] Open
Abstract
Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.
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Affiliation(s)
- Yanying Huo
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Pier Selenica
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Amar H Mahdi
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Department of Physiology, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
| | - Fresia Pareja
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kelly Kyker-Snowman
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Ying Chen
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Rahul Kumar
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Centre for Brain Research, Indian Institute of Science (IISc), Bangalore, India
| | - Arnaud Da Cruz Paula
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Thais Basili
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David N Brown
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xin Pei
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nadeem Riaz
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yongmei Tan
- Stomatological Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yu-Xiu Huang
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Tao Li
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
- Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Nicola J Barnard
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Bing Xia
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
- Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
- Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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Oxidative Stress in Cancer Cell Metabolism. Antioxidants (Basel) 2021; 10:antiox10050642. [PMID: 33922139 PMCID: PMC8143540 DOI: 10.3390/antiox10050642] [Citation(s) in RCA: 272] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/10/2021] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.
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Chun KS, Kim DH, Surh YJ. Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance. Cells 2021; 10:cells10040758. [PMID: 33808242 PMCID: PMC8065762 DOI: 10.3390/cells10040758] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/20/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Redox homeostasis is not only essential for the maintenance of normal physiological functions, but also plays an important role in the growth, survival, and therapy resistance of cancer cells. Altered redox balance and consequent disruption of redox signaling are implicated in the proliferation and progression of cancer cells and their resistance to chemo- and radiotherapy. The nuclear factor erythroid 2 p45-related factor (Nrf2) is the principal stress-responsive transcription factor that plays a pivotal role in maintaining cellular redox homeostasis. Aberrant Nrf2 overactivation has been observed in many cancerous and transformed cells. Uncontrolled amplification of Nrf2-mediated antioxidant signaling results in reductive stress. Some metabolic pathways altered due to reductive stress have been identified as major contributors to tumorigenesis. This review highlights the multifaceted role of reductive stress in cancer development and progression.
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Affiliation(s)
- Kyung-Soo Chun
- College of Pharmacy, Keimyung University, Daegu 42691, Korea;
| | - Do-Hee Kim
- Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do 16227, Korea
- Correspondence: (D.-H.K.); (Y.-J.S.)
| | - Young-Joon Surh
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Korea
- Cancer Research Institute, Seoul National University, Seoul 03080, Korea
- Correspondence: (D.-H.K.); (Y.-J.S.)
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Wang Y, Qi H, Liu Y, Duan C, Liu X, Xia T, Chen D, Piao HL, Liu HX. The double-edged roles of ROS in cancer prevention and therapy. Theranostics 2021; 11:4839-4857. [PMID: 33754031 PMCID: PMC7978298 DOI: 10.7150/thno.56747] [Citation(s) in RCA: 315] [Impact Index Per Article: 78.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/31/2021] [Indexed: 12/20/2022] Open
Abstract
Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.
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41
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Shahavandi M, Shahinfar H, payande N, Sheikhhossein F, Djafarian K, Shab‐Bidar S. The association between dietary antioxidant quality score with metabolic syndrome and its components in Iranian adults: A cross-sectional study. Food Sci Nutr 2021; 9:994-1002. [PMID: 33598182 PMCID: PMC7866576 DOI: 10.1002/fsn3.2067] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 11/15/2022] Open
Abstract
We aimed to investigate whether adherence to dietary antioxidant quality score (DAQS) is associated with metabolic syndrome (MetS) among the Tehranian population. This cross-sectional study was conducted on 270 apparently healthy adults aged between 18 and 45 years old who lived in Tehran, Iran, between February 2017 and December 2018. Participants were categorized based on tertile cut-off points of DAQs. To examine the association between DAQS and MetS and its components, we used multivariable logistic regression analysis in different models. Adherence to DAQS was associated with a significant increase for intake of vitamin B6 (P-value = 0.02), riboflavin (P-value < 0.001), folate (P-value = 0.03), selenium (P-value = 0.03), vitamin D (P-value < 0.001), and calcium (P-value < 0.001). Adherence to DAQS showed a significant decrease for odds of systolic blood pressure (SBP) (OR: 0.17, 95% CI: 0.04, 0.65, P-value = 0.03). We also found that the overall adherence to DAQS was not significantly related to MetS and its other components. In conclusion, although we observed an improvement in SBP with a greater adherence to dietary antioxidant quality score, there was no association between DAQS and metabolic syndrome and its other components.
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Affiliation(s)
- Mahshid Shahavandi
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
- Students’ Scientific Research Center (SSRC)Tehran University of Medical Sciences (TUMS)TehranIran
| | - Hossein Shahinfar
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
- Students’ Scientific Research Center (SSRC)Tehran University of Medical Sciences (TUMS)TehranIran
| | - Nastaran payande
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
| | - Fatemeh Sheikhhossein
- Department of Clinical NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
| | - Kurosh Djafarian
- Department of Clinical NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
| | - Sakineh Shab‐Bidar
- Department of Community NutritionSchool of Nutritional Sciences and DieteticsTehran University of Medical Sciences (TUMS)TehranIran
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Yarmohammadi F, Rezaee R, Karimi G. Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway. Phytother Res 2020; 35:1163-1175. [PMID: 32985744 DOI: 10.1002/ptr.6882] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/01/2020] [Accepted: 08/28/2020] [Indexed: 12/12/2022]
Abstract
Cardiotoxicity is the main concern for long-term use of the doxorubicin (DOX). Reactive oxygen species (ROS) generation leads to oxidative stress that significantly contributes to the cardiac damage induced by DOX. The nuclear factor erythroid 2-related factor (Nrf2) acts as a protective player against DOX-induced myocardial oxidative stress. Several natural compounds (NCs) with anti-oxidative effects, were examined to suppress DOX cardiotoxicity such as asiatic acid, α-linolenic acid, apigenin, baicalein, β-lapachone, curdione, dioscin, ferulic acid, Ganoderma lucidum polysaccharides, genistein, ginsenoside Rg3, indole-3-carbinol, naringenin-7-O-glucoside, neferine, p-coumaric acid, pristimerin, punicalagin, quercetin, sulforaphane, and tanshinone IIA. The present article, reviews NCs that showed protective effects against DOX-induced cardiac injury through induction of Nrf2 signaling pathway.
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Affiliation(s)
- Fatemeh Yarmohammadi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Rezaee
- Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
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Sun X, Wang Y, Ji K, Liu Y, Kong Y, Nie S, Li N, Hao J, Xie Y, Xu C, Du L, Liu Q. NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest. Nucleic Acids Res 2020; 48:9109-9123. [PMID: 32729622 PMCID: PMC7498319 DOI: 10.1093/nar/gkaa631] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 06/21/2020] [Accepted: 07/27/2020] [Indexed: 01/02/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR-CHK1-CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.
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Affiliation(s)
- Xiaohui Sun
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Yan Wang
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Kaihua Ji
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Yang Liu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Yangyang Kong
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Shasha Nie
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Na Li
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Jianxiu Hao
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Yi Xie
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Chang Xu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Liqing Du
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
| | - Qiang Liu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin, China
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44
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Shahinfar H, Shahavandi M, Jibril AT, Djafarian K, Clark CCT, Shab-Bidar S. The Association between Dietary Antioxidant Quality Score and Cardiorespiratory Fitness in Iranian Adults: a Cross-Sectional Study. Clin Nutr Res 2020; 9:171-181. [PMID: 32789147 PMCID: PMC7402974 DOI: 10.7762/cnr.2020.9.3.171] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/05/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022] Open
Abstract
The association between dietary antioxidant quality score (DAQS) and cardiovascular risk factors such as low cardiovascular fitness (CRF) and elevated blood pressure (BP) has rarely been investigated. To investigate the association between DAQS, CRF, and BP. This cross-sectional study was conducted on 270 adult subjects living in Tehran, Iran. Dietary intake was evaluated using a validated food frequency questionnaire. The DAQS was calculated using antioxidant-nutrient intake. Socio-economic status, anthropometric measures, and BP were recorded by a trained interviewer, using standard methods. A significant increase was found in maximal oxygen uptake (p value = 0.01) across tertiles of DAQS. After adjusting for confounders, the association remained unchanged (p value = 0.02). Participants in the highest tertile of DAQS had higher systolic BP (SBP) (p value = 0.01) and diastolic BP (DBP) (p value = 0.03), although adjustment for confounding factors attenuated the results (p value = 0.3 for DBP and p value = 0.6 for SBP). Our results revealed that higher DAQS is associated with better CRF in Iranian adults. Further studies are needed to establish the veracity of our results.
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Affiliation(s)
- Hossein Shahinfar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14167-53955, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran 14167-53955, Iran
| | - Mahshid Shahavandi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14167-53955, Iran
| | - Aliyu Tijani Jibril
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14167-53955, Iran
| | - Kurosh Djafarian
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14167-53955, Iran
| | - Cain C T Clark
- Centre for Sport, Exercise, and Life Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 14167-53955, Iran
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45
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Singh S, Nguyen H, Michels D, Bazinet H, Matkar PN, Liu Z, Esene L, Adam M, Bugyei‐Twum A, Mebrahtu E, Joseph J, Ehsan M, Chen HH, Qadura M, Singh KK. BReast CAncer susceptibility gene 2 deficiency exacerbates oxidized LDL-induced DNA damage and endothelial apoptosis. Physiol Rep 2020; 8:e14481. [PMID: 32638521 PMCID: PMC7340845 DOI: 10.14814/phy2.14481] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/18/2020] [Accepted: 05/15/2020] [Indexed: 12/24/2022] Open
Abstract
Mutations in the tumor suppressor gene BRCA2 (BReast CAncer susceptibility gene 2) predispose carriers to breast, ovarian, and other cancers. In response to DNA damage, BRCA2 participates in homology-directed DNA damage repair to maintain genome stability. Genome-wide association studies have identified an association between BRCA2 single nucleotide polymorphisms and plasma-lipid levels and lipid deregulation in humans. To date, DNA damage, apoptosis, and lipid deregulation are recognized as central pathways for endothelial dysfunction and atherosclerosis; however, the role of BRCA2 in endothelial dysfunction remains to be elucidated. To determine the role of BRCA2 in endothelial dysfunction, BRCA2 was silenced in human umbilical vein endothelial cells (ECs) and assessed for markers of DNA damage, apoptosis, and endothelial function following oxidized low-density lipoprotein (oxLDL) treatment. OxLDL was found to induce significant reactive oxygen species (ROS) production in BRCA2-silenced ECs. This increase in ROS production was associated with exacerbated DNA damage evidenced by increased expression and activation of DNA double-stranded break (DSB) marker γH2AX and reduced RAD51-foci formation-an essential regulator of DSB repair. Increased DSBs were associated with enhanced expression and activation of pro-apoptotic p53 and significant apoptosis in oxLDL-treated BRCA2-silenced ECs. Loss of BRCA2 in ECs was further associated with oxLDL-induced impaired tube-forming potential and eNOS expression. Collectively, the data reveals, for the first time, a novel role of BRCA2 as a regulator of EC survival and function in the setting of oxLDL treatment in vitro. Additionally, the data provide important clues regarding the potential susceptibility of BRCA2 mutation carriers to endothelial dysfunction, atherosclerosis, and other cardiovascular diseases.
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Affiliation(s)
- Shweta Singh
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Hien Nguyen
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
- Anatomy and Cell BiologySchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - David Michels
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Hannah Bazinet
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Pratiek N. Matkar
- Division of CardiologyKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's HospitalTorontoONCanada
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
| | - Zongyi Liu
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Lilian Esene
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Mohamed Adam
- Division of CardiologyKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's HospitalTorontoONCanada
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
| | - Antoinette Bugyei‐Twum
- Division of CardiologyKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's HospitalTorontoONCanada
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
| | - Elizabeth Mebrahtu
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Jameela Joseph
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
- Department of BiologyUniversity of Western OntarioLondonONCanada
| | - Mehroz Ehsan
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
| | - Hao H. Chen
- Division of CardiologyKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's HospitalTorontoONCanada
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
| | - Mohammad Qadura
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
- Vascular SurgeryKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoONCanada
- Department of SurgeryUniversity of TorontoTorontoONCanada
| | - Krishna K. Singh
- Department of Medical BiophysicsSchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
- Anatomy and Cell BiologySchulich School of Medicine and DentistryUniversity of Western OntarioLondonONCanada
- Institute of Medical ScienceUniversity of TorontoTorontoONCanada
- Vascular SurgeryKeenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoONCanada
- Department of SurgeryUniversity of TorontoTorontoONCanada
- Pharmacology and ToxicologyUniversity of TorontoTorontoONCanada
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46
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Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, Castoria G, Migliaccio A. ROS in cancer therapy: the bright side of the moon. Exp Mol Med 2020; 52:192-203. [PMID: 32060354 PMCID: PMC7062874 DOI: 10.1038/s12276-020-0384-2] [Citation(s) in RCA: 1217] [Impact Index Per Article: 243.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/02/2020] [Accepted: 01/03/2020] [Indexed: 12/14/2022] Open
Abstract
Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells. Highly reactive molecules called reactive oxygen species (ROS), which at low levels are natural regulators of important signaling pathways in cells, might be recruited to act as “Trojan horses” to kill cancer cells. Researchers in Italy led by Bruno Perillo of the Institute of Food Sciences in Avelllino review the growing evidence suggesting that stimulating production of natural ROS species could become useful in treating cancer. Although ROS production is elevated in cancer cells it can also promote a natural process called programmed cell death. This normally regulates cell turnover, but could be selectively activated to target diseased cells. The authors discuss molecular mechanisms underlying the potential anti-cancer activity of various ROS-producing strategies, including drugs and light-stimulated therapies. They expect modifying the production of ROS to have potential for developing new treatments.
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Affiliation(s)
- Bruno Perillo
- Istituto di Scienze dell'Alimentazione, C.N.R., 83100, Avellino, Italy. .,Istituto per l'Endocrinologia e l'Oncologia Sperimentale, C.N.R., 80131, Naples, Italy.
| | - Marzia Di Donato
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Antonio Pezone
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Naples, Italy
| | - Erika Di Zazzo
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Pia Giovannelli
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Giovanni Galasso
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Gabriella Castoria
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
| | - Antimo Migliaccio
- Dipartimento di Medicina di Precisione, Università della Campania "L. Vanvitelli", 80138, Naples, Italy
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47
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Kurihara M, Mano T, Saito Y, Murayama S, Toda T, Iwata A. Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies. Brain Sci 2019; 10:brainsci10010007. [PMID: 31861888 PMCID: PMC7016802 DOI: 10.3390/brainsci10010007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/14/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer’s disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick’s disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.
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Affiliation(s)
- Masanori Kurihara
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (M.K.)
- Research Fellow, Japan Society for the Promotion of Science, Tokyo 102-0083, Japan
| | - Tatsuo Mano
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (M.K.)
| | - Yuko Saito
- Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan
| | - Shigeo Murayama
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo 173-0015, Japan
| | - Tatsushi Toda
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (M.K.)
| | - Atsushi Iwata
- Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (M.K.)
- Correspondence: ; Tel.: +81-3-5800-8672
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48
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Hilton HN, Patterson McDonald LJ, Santucci N, van der Bent FR, Silvestri A, Graham JD, Clarke CL. BRCA1 Attenuates Progesterone Effects on Proliferation and NFκB Activation in Normal Human Mammary Epithelial Cells. J Mammary Gland Biol Neoplasia 2019; 24:257-270. [PMID: 31104199 DOI: 10.1007/s10911-019-09431-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 04/21/2019] [Indexed: 12/25/2022] Open
Abstract
Germline mutations in the breast cancer susceptibility gene BRCA1, encoding a tumor suppressor protein, greatly enhance the risk of breast and ovarian cancer. This tissue-specificity implicates the role of ovarian hormones. Indeed, BRCA1 has been demonstrated to regulate the signalling axis of the hormone, progesterone, and its receptor, the progesterone receptor (PR), and progesterone action has been implicated in BRCA1-related tumorigenesis. BRCA1 also plays important roles in oxidative stress and activating nuclear factor kappaB (NFκB) signalling pathways. Like wildtype BRCA1 function, PR signalling has also been shown to inhibit NFκB activation. Although PR and BRCA1 networks are known to interact, their interaction at the level of NFκB activation in the human breast is not understood. This study investigates the effect of reduced BRCA1 expression on proliferation and NFκB activation in human breast cells, and the impact of progesterone on these effects. The major findings are that: 1) Reduced BRCA1 levels inhibit cell growth in normal human mammary cells and breast cancer cells; 2) Reduced BRCA1 levels stimulated inflammatory targets and NFκB activity in normal human mammary cells; 3) Wildtype BRCA1 inhibited the pro-proliferative effects of progesterone in normal mammary epithelial cells, and; 4) Progesterone attenuated BRCA1-mediated NFκB activation in normal human mammary cells. These data have important implications for our understanding of progesterone action in BRCA1 mutation carriers, and how inhibition of this action may potentially delay tumorigenesis or impart a more favourable prognosis.
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Affiliation(s)
- H N Hilton
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia
| | - L J Patterson McDonald
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia
| | - N Santucci
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia
| | - F R van der Bent
- Department of Medicine, Academic Medical Center, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands
| | - A Silvestri
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia
| | - J D Graham
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia.
| | - C L Clarke
- Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School - Westmead, The University of Sydney, Westmead, NSW, 2145, Australia
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49
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BRCA-1 depletion impairs pro-inflammatory polarization and activation of RAW 264.7 macrophages in a NF-κB-dependent mechanism. Mol Cell Biochem 2019; 462:11-23. [DOI: 10.1007/s11010-019-03605-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/08/2019] [Indexed: 12/15/2022]
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50
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Sun X, Wang S, Gai J, Guan J, Li J, Li Y, Zhao J, Zhao C, Fu L, Li Q. SIRT5 Promotes Cisplatin Resistance in Ovarian Cancer by Suppressing DNA Damage in a ROS-Dependent Manner via Regulation of the Nrf2/HO-1 Pathway. Front Oncol 2019; 9:754. [PMID: 31456942 PMCID: PMC6700301 DOI: 10.3389/fonc.2019.00754] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 07/26/2019] [Indexed: 12/21/2022] Open
Abstract
Sirtuin 5 (SIRT5), a mitochondrial class III NAD-dependent deacetylase, plays controversial roles in tumorigenesis and chemoresistance. Accordingly, its role in ovarian cancer development and drug resistance is not fully understood. Here, we demonstrate that SIRT5 is increased in ovarian cancer tissues compared to its expression in normal tissues and this predicts a poor response to chemotherapy. SIRT5 levels were also found to be higher in cisplatin-resistant SKOV-3 and CAOV-3 ovarian cancer cells than in cisplatin-sensitive A2780 cells. Furthermore, this protein was revealed to facilitate ovarian cancer cell growth and cisplatin-resistance in vitro. Mechanistically, we show that SIRT5 contributes to cisplatin resistance in ovarian cancer by suppressing cisplatin-induced DNA damage in a reactive oxygen species (ROS)-dependent manner via regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.
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Affiliation(s)
- Xiaodan Sun
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Shouhan Wang
- Department of Hepatopancreatobiliary Surgery, Jilin Province Cancer Hospital, Changchun, China
| | - Junda Gai
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Jingqian Guan
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Ji Li
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Yizhuo Li
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Jinming Zhao
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China
| | - Chen Zhao
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
| | - Lin Fu
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.,Department of Pathology, The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Qingchang Li
- Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, China.,Department of Pathology, The First Affiliated Hospital, China Medical University, Shenyang, China
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