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1
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Goldschmidt-Clermont PJ, Sevilla BA. Redox and actin, a fascinating story. Redox Biol 2025; 83:103630. [PMID: 40328105 DOI: 10.1016/j.redox.2025.103630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 04/06/2025] [Accepted: 04/06/2025] [Indexed: 05/08/2025] Open
Abstract
Actin is an extraordinarily complex protein whose functions are essential to cell motility, division, contraction, signaling, transport, tissular structures, DNA repair, and many more cellular activities critical to life for both animals and plants. It is one of the most abundant and conserved proteins and it exists in either a soluble, globular (monomeric, G-actin) or an insoluble, self-assembled (polymerized or filamentous actin, F-actin) conformation as a key component of the cytoskeleton. In the early 1990's little, if anything, was known about the impact of reactive oxygen species (ROS) on the biology of actin except that ROS could disrupt the actin cytoskeleton. Instructively, G-actin is susceptible to alteration by ROS, and thus, purification of G-actin is typically performed in the presence of strong antioxidants (like dithiothreitol) to limit its oxidative degradation. In contrast, F-actin is a more stable conformation and thus actin can be kept relatively intact in purified preparations as filaments at low temperature for extended periods of time. Both G- and F-actin interact with a myriad of intracellular proteins and at least with a couple of extracellular proteins, and these interactions are essential to the many actin functions. This review will show how, over the past 30 years, our understanding of the role of ROS for actin biology has evolved from noxious denaturizing agents to remarkable regulators of the actin cytoskeleton in cells and consequent cellular functions.
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2
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Sun Q, Lei X, Yang X. The crosstalk between non-coding RNAs and oxidative stress in cancer progression. Genes Dis 2025; 12:101286. [PMID: 40028033 PMCID: PMC11870203 DOI: 10.1016/j.gendis.2024.101286] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 02/07/2024] [Accepted: 02/21/2024] [Indexed: 03/05/2025] Open
Abstract
As living standards elevate, cancers are appearing in growing numbers among younger individuals globally and these risks escalate with advancing years. One of the reasons is that instability in the cancer genome reduces the effectiveness of conventional drug treatments and chemotherapy, compared with more targeted therapies. Previous research has discovered non-coding RNAs' crucial role in shaping genetic networks involved in cancer cell growth and invasion through their influence on messenger RNA production or protein binding. Additionally, the interaction between non-coding RNAs and oxidative stress, a crucial process in cancer advancement, cannot be overlooked. Essentially, oxidative stress results from the negative effects of radicals within the body and ties directly to cancer gene expression and signaling. Therefore, this review focuses on the mechanism between non-coding RNAs and oxidative stress in cancer progression, which is conducive to finding new cancer treatment strategies.
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Affiliation(s)
- Qiqi Sun
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
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3
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Mateo-Victoriano B, Samaranayake GJ, Pokharel S, Sahayanathan GJ, Jayaraj C, Troccoli CI, Watson DC, Mohsen MG, Guo Y, Kool ET, Rai P. Oncogenic KRAS addiction states differentially influence MTH1 expression and 8-oxodGTPase activity in lung adenocarcinoma. Redox Biol 2025; 82:103610. [PMID: 40184641 PMCID: PMC11999683 DOI: 10.1016/j.redox.2025.103610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 03/11/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
The efficacy of strategies targeting oncogenic RAS, prevalent in lung adenocarcinoma (LUAD), is limited by rapid adaptive resistance mechanisms. These include loss of RAS addiction and hyperactivation of downstream signaling pathways, such as PI3K/AKT. We previously reported that oncogenic RAS-driven LUAD cells possess an enhanced reliance on MTH1, the mammalian 8-oxodGTPase, to prevent genomic incorporation of oxidized nucleotides, and that MTH1 depletion compromises tumorigenesis and oncogenic signaling. Here, we show that elevated MTH1 correlates with poor prognosis in LUAD and that its redox-protective 8-oxodGTPase activity is variably regulated in KRAS-addicted vs. non-addicted states. Multiple oncogenic KRAS mutants or overexpression of wildtype (wt) KRAS increased MTH1 expression. Conversely, KRAS depletion or its inhibition by AMG-510 (sotorasib) decreased MTH1 in KRASG12C-addicted LUAD cells. Separation-of-function MEK/ERK1/2-activating mutants recapitulated the elevated MTH1 expression induced by oncogenic RAS in wt KRAS LUAD cells. However, upon inhibition of the MEK/ERK1/2 pathway, compensatory AKT activation maintained MTH1 expression. Indeed, elevated AKT signaling maintained high MTH1 expression even when KRAS oncoprotein was low. We previously reported that cancer cells possess variable MTH1-specific and MTH1-independent 8-oxodGTPase activity levels. Whereas both ERK1/2 and AKT could regulate MTH1 protein levels in KRAS-addicted cells, only AKT signaling was associated with elevated MTH1-specific 8-oxodGTPase activity under KRAS-low or KRAS non-addicted states. Our studies suggest that despite loss of KRAS dependency, LUAD cells retain the requirement for high MTH1 8-oxodGTPase activity due to redox vulnerabilities associated with AKT signaling. Thus, MTH1 may serve as a novel orthogonal vulnerability in LUAD that has lost KRAS addiction.
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Affiliation(s)
- Beatriz Mateo-Victoriano
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Govindi J Samaranayake
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sheela Pokharel
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Gracy Jenifer Sahayanathan
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Christina Jayaraj
- College of Arts and Sciences, University of Miami, Coral Gables, FL, 33146, USA
| | - Clara I Troccoli
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Dionysios C Watson
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA
| | - Michael G Mohsen
- Department of Chemistry, Stanford University, Stanford, CA, 94305, USA
| | - Yan Guo
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA
| | - Eric T Kool
- Department of Chemistry, Stanford University, Stanford, CA, 94305, USA
| | - Priyamvada Rai
- Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miami, FL, 33136, USA.
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4
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Hounsell C, Fan Y. Death fuels growth: Emerging players bridging apoptosis and cell proliferation in Drosophila and beyond. Semin Cell Dev Biol 2025; 169:103602. [PMID: 40081300 DOI: 10.1016/j.semcdb.2025.103602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/18/2025] [Accepted: 02/23/2025] [Indexed: 03/16/2025]
Abstract
Tissue homeostasis relies on a delicate balance between cell death and proliferation. Apoptosis plays a key role not only in removing damaged cells but also in promoting tissue recovery through a process known as apoptosis-induced proliferation (AiP). This review highlights how caspases, c-Jun N-terminal Kinase (JNK), and Reactive Oxygen Species (ROS) bridge cell death and proliferation, as revealed through studies using Drosophila as a model organism. We also compare these findings with advances in other model systems and discuss their broader implications for tissue regeneration and tumorigenesis.
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Affiliation(s)
- Caitlin Hounsell
- University of Birmingham, School of Biosciences, Birmingham, B15 2TT, UK
| | - Yun Fan
- University of Birmingham, School of Biosciences, Birmingham, B15 2TT, UK.
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5
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Cobley JN, Chatzinikolaou PN, Schmidt CA. The nonlinear cysteine redox dynamics in the i-space: A proteoform-centric theory of redox regulation. Redox Biol 2025; 81:103523. [PMID: 39929052 PMCID: PMC11849597 DOI: 10.1016/j.redox.2025.103523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/27/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
The post-translational redox regulation of protein function by cysteine oxidation controls diverse biological processes, from cell division to death. However, most current site-centric paradigms fail to capture the nonlinear and emergent nature of redox regulation in proteins with multiple cysteines. Here, we present a proteoform-centric theory of redox regulation grounded in the i-space. The i-space encapsulates the theoretical landscape of all possible cysteine proteoforms. Using computational approaches, we quantify the vast size of the abstract i-space, revealing its scale-free architecture-elucidating the disproportionate influence of cysteine-rich proteins. We define mathematical rules governing cysteine proteoform dynamics. Their dynamics are inherently nonlinear, context-dependent, and fundamentally constrained by protein copy numbers. Monte Carlo simulations of the human protein PTP1B reveal extensive i-space sampling beyond site-centric models, supporting the "oxiform conjecture". This conjecture posits that highly oxidised proteoforms, molecules bearing multiple oxidised cysteines, are central to redox regulation. In support, even 90%-reduced proteomes can house vast numbers of unique, potentially functioanlly diverse, oxiforms. This framework offers a transformative lens for understanding the redox biology of proteoforms.
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Liang Z, Zhao S, Liu Y, Cheng C. The promise of mitochondria in the treatment of glioblastoma: a brief review. Discov Oncol 2025; 16:142. [PMID: 39924629 PMCID: PMC11807951 DOI: 10.1007/s12672-025-01891-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 02/03/2025] [Indexed: 02/11/2025] Open
Abstract
Glioblastoma (GBM) is a prevalent and refractory type of brain tumor. Over the past two decades, there have been minimal advancements in GBM therapy. The current standard treatment involves surgical excision followed by radiation and chemotherapy. Compared to other tumors, GBM is more challenging to treat due to the presence of glioma stem-like cells (GSCs) and the blood-brain barrier, resulting in an extremely low survival rate. Mitochondria play a critical role in tumor respiration, metabolism, and multiple signaling pathways involved in tumor formation, progression, and cell apoptosis. Consequently, mitochondria represent promising targets for developing novel anticancer agents, including those targeting oxidative phosphorylation, reactive oxygen species (ROS), mitochondrial transfer, and mitophagy. This review outlines the mitochondrial-related therapeutic targets in GBM, highlighting the potential of mitochondria as a target for GBM treatment.
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Affiliation(s)
- Zhuo Liang
- Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Songyun Zhao
- Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yuankun Liu
- Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Chao Cheng
- Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
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Dai M, Lin B, Li H, Wang Y, Wu M, Wei Y, Zeng W, Qu L, Cang C, Wang X. Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy. Mol Cell Biochem 2025; 480:1209-1224. [PMID: 38951379 DOI: 10.1007/s11010-024-05054-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 06/12/2024] [Indexed: 07/03/2024]
Abstract
Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.
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MESH Headings
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/genetics
- Humans
- Transient Receptor Potential Channels/metabolism
- Transient Receptor Potential Channels/genetics
- Transient Receptor Potential Channels/antagonists & inhibitors
- Autophagy/drug effects
- Animals
- Lysosomes/metabolism
- Lysosomes/pathology
- Mice
- Antineoplastic Agents/pharmacology
- Reactive Oxygen Species/metabolism
- Drug Resistance, Neoplasm/drug effects
- Neoplasm Proteins/metabolism
- Neoplasm Proteins/genetics
- Neoplasm Proteins/antagonists & inhibitors
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
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Affiliation(s)
- Meifang Dai
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, China
| | - Bingqian Lin
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Hao Li
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Youming Wang
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Miaomiao Wu
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yanan Wei
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Wenping Zeng
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, China
| | - Lili Qu
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, China.
| | - Chunlei Cang
- CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China.
| | - Xingbing Wang
- Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
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8
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Zhou S, Zhao Z, Wang Z, Xu H, Li Y, Xu K, Li W, Yang J. Cancer-associated fibroblasts in carcinogenesis. J Transl Med 2025; 23:50. [PMID: 39806363 PMCID: PMC11727299 DOI: 10.1186/s12967-025-06071-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
In contemporary times, cancer poses the most significant threat to human life and safety. Scientists have relentlessly pursued the intricacies of carcinogenesis and explored ways to prevent and treat cancer. Carcinogenesis is a complex, multi-faceted, and multi-stage process, with numerous underlying causes, including inflammation and fibrosis. Cancer-associated fibroblasts (CAFs), however, occupy a pivotal and substantial role within the tumor microenvironment, facilitating carcinogenesis through diverse mechanisms such as creating inflammation, fostering a fibrotic tumor microenvironment, and immunosuppression. In this paper, we introduce the concept of carcinogenesis, explain its causes, describe the characteristics of CAFs and their sources, and highlight the roles and mechanisms of CAFs in promoting carcinogenesis. Ultimately, our aim is to contribute to the development of novel therapeutic strategies for cancer treatment.
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Affiliation(s)
- Shufen Zhou
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Zekun Zhao
- Department of General Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Zhaojun Wang
- Department of Thyroid and Breast Surgery, The DingLi Clinical, The Wenzhou Central Hospital, College of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Hanzheng Xu
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yijie Li
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Ke Xu
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
- Wenzhou Institute of Shanghai University, Wenzhou, 325000, China.
| | - Wei Li
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
| | - Jiahua Yang
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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9
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Petrachkova T, Soldatkina O, Leduy L, Nepveu A. The BCL11A transcription factor stimulates the enzymatic activities of the OGG1 DNA glycosylase. Biol Chem 2024; 405:711-726. [PMID: 39272221 PMCID: PMC11712033 DOI: 10.1515/hsz-2024-0088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024]
Abstract
The BCL11A transcription factor has previously been shown to interact with and stimulate the enzymatic activities of the NTHL1 DNA glycosylase and Pol β polymerase. Here we show that BCL11A and a smaller peptide encompassing amino acids 160 to 520 can interact with the 8-oxoguanine DNA glycosylase, OGG1, increase the binding of OGG1 to DNA that contains an 8-oxoguanine base and stimulate the glycosylase activity of OGG1. Following BCL11A knockdown, we observed an increase in oxidized purines in the genome using comet assays, while immunoassays reveal an increase in 8-oxoG bases. Structure-function analysis indicates that the stimulation of OGG1 by BCL11A requires the zinc fingers 1, 2 and 3 as well as the proline-rich region between the first and second zing finger, but a glutamate-rich region downstream of zinc finger 3 is dispensable. Ectopic expression of a small peptide that contains the three zinc fingers can rescue the increase in 8-oxoguanine caused by BCL11A knockdown. These findings, together with previous results showing that BCL11A stimulates the enzymatic activities of NTHL1 and the Pol β polymerase, suggest that high expression of BCL11A is important to protect cancer cells against oxidative DNA damage.
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Affiliation(s)
- Tetiana Petrachkova
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Olha Soldatkina
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Lam Leduy
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
| | - Alain Nepveu
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Medicine, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
- Departments of Oncology, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada
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Keith WC, Hemmati F, Vaghasiya RS, Amiri F, Mistriotis P. Differential Effects of Confinement-Induced ROS Accumulation on Highly Motile Cancerous and Non-Cancerous Cells. AIChE J 2024; 70:e18598. [PMID: 40099227 PMCID: PMC11913314 DOI: 10.1002/aic.18598] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/20/2024] [Indexed: 03/19/2025]
Abstract
In vivo, migrating cells often encounter microenvironments that impose spatial constraints, leading to cell and nuclear deformation. As confinement-induced DNA damage has been linked to the accumulation of reactive oxygen species (ROS), we sought to investigate the impact of oxidative stress on cell behavior within confined spaces. Using microchannel devices that enable control of the degree and duration of cell confinement, we demonstrate that confined migration increases ROS levels in both HT-1080 fibrosarcoma cells and human dermal fibroblasts. Treatment with the antioxidant N-Acetyl-L-cysteine (NAC) counteracts confinement-induced ROS accumulation, suppressing p53 activation and supporting cell survival in both cell lines. This intervention preferentially reduces dorsal perinuclear actin fibers in confined cancer cells. Loss of these fibers is associated with reduced nuclear rupture frequency and increased confined migration. Collectively, this work provides insights into the differential effects of ROS on cancerous and non-cancerous cells and suggests that antioxidants may support tumor progression.
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Affiliation(s)
| | - Farnaz Hemmati
- Department of Chemical Engineering, Auburn University, Auburn AL, 36849, USA
| | | | - Farshad Amiri
- Department of Chemical Engineering, Auburn University, Auburn AL, 36849, USA
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11
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Liu F, Liu L, Wei P, Yi T. A reactive oxygen species-triggerable theranostic prodrug system. J Control Release 2024; 376:961-971. [PMID: 39476874 DOI: 10.1016/j.jconrel.2024.10.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 10/08/2024] [Accepted: 10/27/2024] [Indexed: 11/09/2024]
Abstract
Abnormally elevated levels of reactive oxygen species (ROS) are considered one of the characteristics of tumors and have been extensively employed in the construction of tumor-activated prodrugs. However, ideal ROS-activated molecular triggers that possess high sensitivity and easy functionalization for tailoring specific prodrugs, remain scarce. In this work, we developed a highly reactive oxygen species (hROS, such as •OH, ONOO- and HOCl)-responsive molecular trigger (namely FDROS-4) through the conjunction of methylene blue (MB) and 2, 6-bis (hydroxymethyl) aniline via urea bond, integrating imaging and therapeutic functions. FDROS-4 could be readily modified as multifunctional prodrugs and efficiently activated by hROS, leading to the release of near-infrared emissive MB and parent drugs. By using chlorambucil as a model drug and incorporating varying numbers of galactose as liver-targeting ligands, we designed and synthesized a series of prodrugs named FDROS-6, FDROS-7, and FDROS-8. The optimal prodrug, FDROS-7, could self-assemble into monocomponent nanoparticles, exhibiting enhanced biocompatibility and therapeutic efficacy compared to the parent drug. This hROS-activated molecular trigger holds promise for the development of stimulus-responsive prodrugs in chemotherapy.
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Affiliation(s)
- Feiyang Liu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China; Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning 530004, China
| | - Lingyan Liu
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China
| | - Peng Wei
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China.
| | - Tao Yi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, China.
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12
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Chen A, Huang H, Fang S, Hang Q. ROS: A "booster" for chronic inflammation and tumor metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189175. [PMID: 39218404 DOI: 10.1016/j.bbcan.2024.189175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Reactive oxygen species (ROS) are a group of highly active molecules produced by normal cellular metabolism and play a crucial role in the human body. In recent years, researchers have increasingly discovered that ROS plays a vital role in the progression of chronic inflammation and tumor metastasis. The inflammatory tumor microenvironment established by chronic inflammation can induce ROS production through inflammatory cells. ROS can then directly damage DNA or indirectly activate cellular signaling pathways to promote tumor metastasis and development, including breast cancer, lung cancer, liver cancer, colorectal cancer, and so on. This review aims to elucidate the relationship between ROS, chronic inflammation, and tumor metastasis, explaining how chronic inflammation can induce tumor metastasis and how ROS can contribute to the evolution of chronic inflammation toward tumor metastasis. Interestingly, ROS can have a "double-edged sword" effect, promoting tumor metastasis in some cases and inhibiting it in others. This article also highlights the potential applications of ROS in inhibiting tumor metastasis and enhancing the precision of tumor-targeted therapy. Combining ROS with nanomaterials strategies may be a promising approach to enhance the efficacy of tumor treatment.
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Affiliation(s)
- Anqi Chen
- Medical College, Yangzhou University, Yangzhou 225009, China
| | - Haifeng Huang
- Department of Laboratory Medicine, The First People's Hospital of Yancheng, Yancheng 224006, China; Department of Laboratory Medicine, Yancheng Clinical Medical College of Jiangsu University, Yancheng 224006, China
| | - Sumeng Fang
- School of Mathematics, Tianjin University, Tianjin 300350, China
| | - Qinglei Hang
- Jiangsu Provincial Innovation and Practice Base for Postdoctors, Suining People's Hospital, Affiliated Hospital of Xuzhou Medical University, Suining 221200, China; Key Laboratory of Jiangsu Province University for Nucleic Acid & Cell Fate Manipulation, Yangzhou University, Yangzhou 225009, China; Department of Laboratory Medicine, Medical College, Yangzhou University, Yangzhou 225009, China.
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Kaur C, Sahu SK, Bansal K, DeLiberto LK, Zhang J, Tewari D, Bishayee A. Targeting Peroxisome Proliferator-Activated Receptor-β/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy. Antioxid Redox Signal 2024; 41:342-395. [PMID: 38299535 DOI: 10.1089/ars.2023.0442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-β/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-β/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-β/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-β/δ.
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Affiliation(s)
- Charanjit Kaur
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sanjeev Kumar Sahu
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Keshav Bansal
- Department of Pharmaceutics, Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Lindsay K DeLiberto
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Jie Zhang
- College of Food Science and Engineering, Jilin University, Changchun, China
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
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14
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Shrivastava S, Bahuguna T, Mondal S, Kumar S, Mathew B, Jeengar MK, Naidu VGM. Attenuation of adjuvant-induced arthritis with carnosic acid by inhibiting mPGES-1, COX-2, and bone loss in male SD rats. Immunopharmacol Immunotoxicol 2024:1-12. [PMID: 39013842 DOI: 10.1080/08923973.2024.2377984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 07/04/2024] [Indexed: 07/18/2024]
Abstract
OBJECTIVE Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by joint swelling, cartilage erosion, and bone destruction. This study investigated the therapeutic efficacy of Carnosic acid (CA), a natural compound with anti-inflammatory and antioxidant properties, in an adjuvant-induced arthritis model. METHODS Paw swelling and arthritis index were measured. Oxidative stress markers, including lipid peroxidation and antioxidant enzyme levels, were assessed. Synovial tissue was analyzed for pro-inflammatory markers using real-time Q-PCR and Western blotting. The expression of mPGES-1 was determined by Western blotting. Peripheral neuropathic pain was assessed using cold and mechanical allodynia tests. Bone loss was quantitatively assessed through microcomputed tomography (μCT) scanning of femurs and X-ray radiography. Indomethacin-induced gastric ulcers were evaluated. Molecular docking studies were conducted to analyze the binding affinity of CA to mPGES-1. RESULTS The CA treatment not only demonstrated a significant reduction in joint inflammation and paw swelling but also mitigated oxidative stress and improved the antioxidant defence system. CA inhibited microsomal prostaglandin E synthase-1 (mPGES-1) expression and the expression of pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenases-2 (COX-2), thus attenuating the arthritis symptoms without severe gastrointestinal side effects. Additionally, it inhibited the expression of pro-inflammatory molecules such as iNOS and COX-2, contributing to the reduction of arthritis symptoms. Notably, CA treatment prevented the common side effects of traditional RA treatments like corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), including weight loss, bone degradation, and gastric ulcers. CONCLUSIONS These findings suggest that CA, through specific enzyme inhibition, offers a compelling alternative therapeutic approach for RA. Further research is warranted to explore the potential of CA in other arthritis models and its suitability for human RA treatment.
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Affiliation(s)
- Shweta Shrivastava
- School of Pharmacy, School of Health and Allied Sciences, ARKA JAIN University, Gamharia, Seraikela Kharsawan, Jharkhand, India
| | - Tribhuwan Bahuguna
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research Institute (NIPER), Balanagar, Hyderabad, India
| | - Sudipto Mondal
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research Institute (NIPER), Balanagar, Hyderabad, India
| | - Sunil Kumar
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, Kerala, India
| | - Manish Kumar Jeengar
- Department of Pharmacology, Amrita School of Pharmacy, AIMS Health Sciences Campus, Kochi, Kerala, India
| | - V G M Naidu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research Institute (NIPER), Assam, India
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15
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Fujikawa Y, Kawai H, Suzuki T, Kamiya H. Visualization of oxidized guanine nucleotides accumulation in living cells with split MutT. Nucleic Acids Res 2024; 52:6532-6542. [PMID: 38738661 PMCID: PMC11194108 DOI: 10.1093/nar/gkae371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/14/2024] [Accepted: 04/25/2024] [Indexed: 05/14/2024] Open
Abstract
Cancer cells produce vast quantities of reactive oxygen species, leading to the accumulation of toxic nucleotides as 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). The human MTH1 protein catalyzes the hydrolysis of 8-oxo-dGTP, and cancer cells are dependent on MTH1 for their survival. MTH1 inhibitors are possible candidates for a class of anticancer drugs; however, a reliable screening system using live cells has not been developed. Here we report a visualization method for 8-oxo-dGTP and its related nucleotides in living cells. Escherichia coli MutT, a functional homologue of MTH1, is divided into the N-terminal (1-95) and C-terminal (96-129) parts (Mu95 and 96tT, respectively). Mu95 and 96tT were fused to Ash (assembly helper tag) and hAG (Azami Green), respectively, to visualize the nucleotides as fluorescent foci formed upon the Ash-hAG association. The foci were highly increased when human cells expressing Ash-Mu95 and hAG-96tT were treated with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-dGTP. The foci formation by 8-oxo-dG(TP) was strikingly enhanced by the MTH1 knockdown. Moreover, known MTH1 inhibitors and oxidizing reagents also increased foci. This is the first system that visualizes damaged nucleotides in living cells, provides an excellent detection method for the oxidized nucleotides and oxidative stress, and enables high throughput screening for MTH1 inhibitors.
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Affiliation(s)
- Yoshihiro Fujikawa
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Hidehiko Kawai
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Tetsuya Suzuki
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Hiroyuki Kamiya
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
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16
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Yapici FI, Bebber CM, von Karstedt S. A guide to ferroptosis in cancer. Mol Oncol 2024; 18:1378-1396. [PMID: 38590214 PMCID: PMC11161738 DOI: 10.1002/1878-0261.13649] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/20/2024] [Accepted: 03/26/2024] [Indexed: 04/10/2024] Open
Abstract
Ferroptosis is a newly identified iron-dependent type of regulated cell death that can also be regarded as death caused by the specific collapse of the lipid antioxidant defence machinery. Ferroptosis has gained increasing attention as a potential therapeutic strategy for therapy-resistant cancer types. However, many ferroptosis-inducing small molecules do not reach the pharmacokinetic requirements for their effective clinical use yet. Nevertheless, their clinical optimization is under development. In this review, we summarize the current understanding of molecular pathways regulating ferroptosis, how cells protect themselves from the induction of ferroptotic cell death, and how a better understanding of cancer cell metabolism can represent vulnerabilities for ferroptosis-based therapies. Lastly, we discuss the context-dependent effect of ferroptosis on various cell types within the tumor microenvironment and address controversies on how tissue ferroptosis might impact systemic cancer immunity in a paracrine manner.
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Affiliation(s)
- Fatma Isil Yapici
- Department of Translational Genomics, Faculty of Medicine and University Hospital CologneUniversity of CologneGermany
- CECAD Cluster of ExcellenceUniversity of CologneGermany
| | - Christina M. Bebber
- Department of Translational Genomics, Faculty of Medicine and University Hospital CologneUniversity of CologneGermany
- CECAD Cluster of ExcellenceUniversity of CologneGermany
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital CologneUniversity of CologneGermany
- CECAD Cluster of ExcellenceUniversity of CologneGermany
- Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital CologneUniversity of CologneGermany
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17
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Yao L, Zhu X, Shan Y, Zhang L, Yao J, Xiong H. Recent Progress in Anti-Tumor Nanodrugs Based on Tumor Microenvironment Redox Regulation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310018. [PMID: 38269480 DOI: 10.1002/smll.202310018] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/30/2023] [Indexed: 01/26/2024]
Abstract
The growth state of tumor cells is strictly affected by the specific abnormal redox status of the tumor microenvironment (TME). Moreover, redox reactions at the biological level are also central and fundamental to essential energy metabolism reactions in tumors. Accordingly, anti-tumor nanodrugs targeting the disruption of this abnormal redox homeostasis have become one of the hot spots in the field of nanodrugs research due to the effectiveness of TME modulation and anti-tumor efficiency mediated by redox interference. This review discusses the latest research results of nanodrugs in anti-tumor therapy, which regulate the levels of oxidants or reductants in TME through a variety of therapeutic strategies, ultimately breaking the original "stable" redox state of the TME and promoting tumor cell death. With the gradual deepening of study on the redox state of TME and the vigorous development of nanomaterials, it is expected that more anti-tumor nano drugs based on tumor redox microenvironment regulation will be designed and even applied clinically.
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Affiliation(s)
- Lan Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Xiang Zhu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Yunyi Shan
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Liang Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Jing Yao
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
| | - Hui Xiong
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, P. R. China
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18
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Bischof L, Schweitzer F, Heinisch JJ. Functional Conservation of the Small GTPase Rho5/Rac1-A Tale of Yeast and Men. Cells 2024; 13:472. [PMID: 38534316 PMCID: PMC10969153 DOI: 10.3390/cells13060472] [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: 02/17/2024] [Revised: 03/02/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
Small GTPases are molecular switches that participate in many essential cellular processes. Amongst them, human Rac1 was first described for its role in regulating actin cytoskeleton dynamics and cell migration, with a close relation to carcinogenesis. More recently, the role of Rac1 in regulating the production of reactive oxygen species (ROS), both as a subunit of NADPH oxidase complexes and through its association with mitochondrial functions, has drawn attention. Malfunctions in this context affect cellular plasticity and apoptosis, related to neurodegenerative diseases and diabetes. Some of these features of Rac1 are conserved in its yeast homologue Rho5. Here, we review the structural and functional similarities and differences between these two evolutionary distant proteins and propose yeast as a useful model and a device for high-throughput screens for specific drugs.
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Affiliation(s)
| | | | - Jürgen J. Heinisch
- AG Genetik, Fachbereich Biologie/Chemie, University of Osnabrück, Barbarastrasse 11, D-49076 Osnabrück, Germany; (L.B.); (F.S.)
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19
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Wang Z, Zhang Y, Liao Z, Huang M, Shui X. The potential of aryl hydrocarbon receptor as receptors for metabolic changes in tumors. Front Oncol 2024; 14:1328606. [PMID: 38434684 PMCID: PMC10904539 DOI: 10.3389/fonc.2024.1328606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/29/2024] [Indexed: 03/05/2024] Open
Abstract
Cancer cells can alter their metabolism to meet energy and molecular requirements due to unfavorable environments with oxygen and nutritional deficiencies. Therefore, metabolic reprogramming is common in a tumor microenvironment (TME). Aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor, which can be activated by many exogenous and endogenous ligands. Multiple AhR ligands can be produced by both TME and tumor cells. By attaching to various ligands, AhR regulates cancer metabolic reprogramming by dysregulating various metabolic pathways, including glycolysis, lipid metabolism, and nucleotide metabolism. These regulated pathways greatly contribute to cancer cell growth, metastasis, and evading cancer therapies; however, the underlying mechanisms remain unclear. Herein, we review the relationship between TME and metabolism and describe the important role of AhR in cancer regulation. We also focus on recent findings to discuss the idea that AhR acts as a receptor for metabolic changes in tumors, which may provide new perspectives on the direction of AhR research in tumor metabolic reprogramming and future therapeutic interventions.
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Affiliation(s)
- Zhiying Wang
- Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yuanqi Zhang
- Department of Breast Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Zhihong Liao
- Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Mingzhang Huang
- Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Xiaorong Shui
- Laboratory of Vascular Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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20
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Herb M. NADPH Oxidase 3: Beyond the Inner Ear. Antioxidants (Basel) 2024; 13:219. [PMID: 38397817 PMCID: PMC10886416 DOI: 10.3390/antiox13020219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed.
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Affiliation(s)
- Marc Herb
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50935 Cologne, Germany;
- German Centre for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany
- Cologne Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50931 Cologne, Germany
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21
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Parascandolo A, Benincasa G, Corcione F, Laukkanen MO. ERK2 Is a Promoter of Cancer Cell Growth and Migration in Colon Adenocarcinoma. Antioxidants (Basel) 2024; 13:119. [PMID: 38247543 PMCID: PMC10812609 DOI: 10.3390/antiox13010119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/14/2024] [Accepted: 01/16/2024] [Indexed: 01/23/2024] Open
Abstract
ERK1/2 phosphorylation is frequently downregulated in the early phase of colon tumorigenesis with subsequent activation of ERK5. In the current work, we studied the advantages of ERK1/2 downregulation for tumor growth by dissecting the individual functions of ERK1 and ERK2. The patient sample data demonstrated decreased ERK1/2 phosphorylation in the early phase of tumorigenesis followed by increased phosphorylation in late-stage colon adenocarcinomas with intratumoral invasion or metastasis. In vitro results indicated that SOD3-mediated coordination of small GTPase RAS regulatory genes inhibited RAS-ERK1/2 signaling. In vitro and in vivo studies suggested that ERK2 has a more prominent role in chemotactic invasion, collective migration, and cell proliferation than ERK1. Of note, simultaneous ERK1 and ERK2 expression inhibited collective cell migration and proliferation but tended to promote invasion, suggesting that ERK1 controls ERK2 function. According to the present data, phosphorylated ERK1/2 at the early phase of colon adenocarcinoma limits tumor mass expansion, whereas reactivation of the kinases at the later phase of colon carcinogenesis is associated with the initiation of metastasis. Additionally, our results suggest that ERK1 is a regulatory kinase that coordinates ERK2-promoted chemotactic invasion, collective migration, and cell proliferation. Our findings indicate that ROS, especially H2O2, are associated with the regulation of ERK1/2 phosphorylation in colon cancer by either increasing or decreasing kinase activity. These data suggest that ERK2 has a growth-promoting role and ERK1 has a regulatory role in colon tumorigenesis, which could lead to new avenues in the development of cancer therapy.
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Affiliation(s)
- Alessia Parascandolo
- Department of Translational Medical Sciences, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy;
| | | | | | - Mikko O. Laukkanen
- Department of Translational Medical Sciences, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy;
- Center for Experimental Endocrinology and Oncology (IEOS), CNR-IEOS, Via Pansini 5, 80131 Naples, Italy
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22
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Zuchegna C, Leone S, Romano A, Porcellini A, Messina S. KRAS is a molecular determinant of platinum responsiveness in glioblastoma. BMC Cancer 2024; 24:77. [PMID: 38225605 PMCID: PMC10789061 DOI: 10.1186/s12885-023-11758-6] [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: 08/26/2023] [Accepted: 12/13/2023] [Indexed: 01/17/2024] Open
Abstract
BACKGROUND KRAS is the undisputed champion of oncogenes, and despite its prominent role in oncogenesis as mutated gene, KRAS mutation appears infrequent in gliomas. Nevertheless, gliomas are considered KRAS-driven cancers due to its essential role in mouse malignant gliomagenesis. Glioblastoma is the most lethal primary brain tumor, often associated with disturbed RAS signaling. For newly diagnosed GBM, the current standard therapy is alkylating agent chemotherapy combined with radiotherapy. Cisplatin is one of the most effective anticancer drugs and is used as a first-line treatment for a wide spectrum of solid tumors (including medulloblastoma and neuroblastoma) and many studies are currently focused on new delivery modalities of effective cisplatin in glioblastoma. Its mechanism of action is mainly based on DNA damage, inducing the formation of DNA adducts, triggering a series of signal-transduction pathways, leading to cell-cycle arrest, DNA repair and apoptosis. METHODS Long-term cultures of human glioblastoma, U87MG and U251MG, were either treated with cis-diamminedichloroplatinum (cisplatin, CDDP) and/or MEK-inhibitor PD98059. Cytotoxic responses were assessed by cell viability (MTT), protein expression (Western Blot), cell cycle (PI staining) and apoptosis (TUNEL) assays. Further, gain-of-function experiments were performed with cells over-expressing mutated hypervariable region (HVR) KRASG12V plasmids. RESULTS Here, we studied platinum-based chemosensitivity of long-term cultures of human glioblastoma from the perspective of KRAS expression, by using CDDP and MEK-inhibitor. Endogenous high KRAS expression was assessed at transcriptional (qPCR) and translational levels (WB) in a panel of primary and long-term glioblastoma cultures. Firstly, we measured immediate cellular adjustment through direct regulation of protein concentration of K-Ras4B in response to cisplatin treatment. We found increased endogenous protein abundance and involvement of the effector pathway RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade. Moreover, as many MEK inhibitors are currently being clinically evaluated for the treatment of high-grade glioma, so we concomitantly tested the effect of the potent and selective non-ATP-competitive MEK1/2 inhibitor (PD98059) on cisplatin-induced chemosensitivity in these cells. Cell-cycle phase distribution was examined using flow cytometry showing a significant cell-cycle arrest in both cultures at different percentage, which is modulated by MEK inhibition. Cisplatin-induced cytotoxicity increased sub-G1 percentage and modulates G2/M checkpoint regulators cyclins D1 and A. Moreover, ectopic expression of a constitutively active KRASG12V rescued CDDP-induced apoptosis and different HVR point mutations (particularly Ala 185) reverted this phenotype. CONCLUSION These findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as 'actionable target' of cisplatin-based chemotherapy for glioblastoma.
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Affiliation(s)
- Candida Zuchegna
- Department of Biology, Federico II University of Naples, 80126, Naples, Italy
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Antonella Romano
- Department of Biology, Federico II University of Naples, 80126, Naples, Italy
| | - Antonio Porcellini
- Department of Biology, Federico II University of Naples, 80126, Naples, Italy
| | - Samantha Messina
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.
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Chattopadhyay M, Chanda A, Pal B. Unravelling the Nexus: Mitochondrial Oxidative Stress, Tumour Microenvironment, and Escape from Immune Surveillance. CANCER DRUG DISCOVERY AND DEVELOPMENT 2024:255-286. [DOI: 10.1007/978-3-031-66421-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
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24
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Chen J, Cui X, Fang N, Wu Y, Yu S, Xiao D. Methionine-CBS axis promotes intracellular ROS levels by reprogramming serine metabolism. FASEB J 2023; 37:e23268. [PMID: 37889798 DOI: 10.1096/fj.202300804rrrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 09/29/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023]
Abstract
As a non-essential amino acid, cysteine could be obtained through both exogenous uptake and endogenous de novo synthesis pathways. Research has demonstrated that restricting the uptake of cystine could result in a depletion of intracellular cysteine and glutathione, ultimately leading to an increase in intracellular reactive oxygen species (ROS) levels. However, the role of methionine in regulating intracellular ROS levels is currently unclear. Here, we want to explore the role of methionine in regulating intracellular ROS levels. We found that methionine restriction could lead to a decrease in intracellular ROS levels, while supplementation with SAM can restore these levels through flow cytometry. Mechanically, we found that the methionine-SAM axis relies on CBS when regulating intracellular ROS levels. Furthermore, we speculate and prove that the methionine-SAM-CBS axis alters the metabolism of serine, thereby reducing intracellular reductive power, therefore promoting intracellular ROS levels through changing metabolite levels and genetic methods. Finally, our study revealed that high expression of CBS in tumor cells could lead to increased intracellular ROS levels, ultimately resulting in faster proliferation rates. Together, our study confirmed that methionine plays a promoting role in the regulation of intracellular ROS levels.
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Affiliation(s)
- Jingyun Chen
- Cancer Center, The First Hospital of Jilin university, Changchun, China
| | - Xiangyan Cui
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ning Fang
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yu Wu
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
| | - Shujian Yu
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
| | - Dong Xiao
- Department of Otolaryngology-Head and Neck Surgery, The First Hospital of Jilin University, Changchun, China
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Przygoda M, Bartusik-Aebisher D, Dynarowicz K, Cieślar G, Kawczyk-Krupka A, Aebisher D. Cellular Mechanisms of Singlet Oxygen in Photodynamic Therapy. Int J Mol Sci 2023; 24:16890. [PMID: 38069213 PMCID: PMC10706571 DOI: 10.3390/ijms242316890] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
In this review, we delve into the realm of photodynamic therapy (PDT), an established method for combating cancer. The foundation of PDT lies in the activation of a photosensitizing agent using specific wavelengths of light, resulting in the generation of reactive oxygen species (ROS), notably singlet oxygen (1O2). We explore PDT's intricacies, emphasizing its precise targeting of cancer cells while sparing healthy tissue. We examine the pivotal role of singlet oxygen in initiating apoptosis and other cell death pathways, highlighting its potential for minimally invasive cancer treatment. Additionally, we delve into the complex interplay of cellular components, including catalase and NOX1, in defending cancer cells against PDT-induced oxidative and nitrative stress. We unveil an intriguing auto-amplifying mechanism involving secondary singlet oxygen production and catalase inactivation, offering promising avenues for enhancing PDT's effectiveness. In conclusion, our review unravels PDT's inner workings and underscores the importance of selective illumination and photosensitizer properties for achieving precision in cancer therapy. The exploration of cellular responses and interactions reveals opportunities for refining and optimizing PDT, which holds significant potential in the ongoing fight against cancer.
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Affiliation(s)
- Maria Przygoda
- Students English Division Science Club, Medical College of The University of Rzeszów, 35-315 Rzeszów, Poland;
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College of The University of Rzeszów, 35-310 Rzeszów, Poland;
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland;
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland;
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The University of Rzeszów, 35-959 Rzeszów, Poland
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26
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Cobley JN. 50 shades of oxidative stress: A state-specific cysteine redox pattern hypothesis. Redox Biol 2023; 67:102936. [PMID: 37875063 PMCID: PMC10618833 DOI: 10.1016/j.redox.2023.102936] [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: 09/25/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023] Open
Abstract
Oxidative stress is biochemically complex. Like primary colours, specific reactive oxygen species (ROS) and antioxidant inputs can be mixed to create unique "shades" of oxidative stress. Even a minimal redox module comprised of just 12 (ROS & antioxidant) inputs and 3 outputs (oxidative damage, cysteine-dependent redox-regulation, or both) yields over half a million "shades" of oxidative stress. The present paper proposes the novel hypothesis that: state-specific shades of oxidative stress, such as a discrete disease, are associated with distinct tell-tale cysteine oxidation patterns. The patterns are encoded by many parameters, from the identity of the oxidised proteins, the cysteine oxidation type, and magnitude. The hypothesis is conceptually grounded in distinct ROS and antioxidant inputs coalescing to produce unique cysteine oxidation outputs. And considers the potential biological significance of the holistic cysteine oxidation outputs. The literature supports the existence of state-specific cysteine oxidation patterns. Measuring and manipulating these patterns offer promising avenues for advancing oxidative stress research. The pattern inspired hypothesis provides a framework for understanding the complex biochemical nature of state-specific oxidative stress.
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Affiliation(s)
- James N Cobley
- Cysteine redox technology Group, Life Science Innovation Centre, University of the Highlands and Islands, Inverness, IV2 5NA, Scotland, UK.
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27
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Xiang M, Liu L, Wu T, Wei B, Liu H. RNA-binding proteins in degenerative joint diseases: A systematic review. Ageing Res Rev 2023; 86:101870. [PMID: 36746279 DOI: 10.1016/j.arr.2023.101870] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/12/2023] [Accepted: 01/27/2023] [Indexed: 02/07/2023]
Abstract
RNA-binding proteins (RBPs), which are conserved proteins comprising multiple intermediate sequences, can interact with proteins, messenger RNA (mRNA) of coding genes, and non-coding RNAs to perform different biological functions, such as the regulation of mRNA stability, selective polyadenylation, and the management of non-coding microRNA (miRNA) synthesis to affect downstream targets. This article will highlight the functions of RBPs, in degenerative joint diseases (intervertebral disc degeneration [IVDD] and osteoarthritis [OA]). It will reviews the latest advancements on the regulatory mechanism of RBPs in degenerative joint diseases, in order to understand the pathophysiology, early diagnosis and treatment of OA and IVDD from a new perspective.
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Affiliation(s)
- Min Xiang
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Ling Liu
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Tingrui Wu
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
| | - Bo Wei
- Department of Orthopedics, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China.
| | - Huan Liu
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China.
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28
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Ghareghomi S, Moosavi-Movahedi F, Saso L, Habibi-Rezaei M, Khatibi A, Hong J, Moosavi-Movahedi AA. Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer. Antioxidants (Basel) 2023; 12:antiox12030735. [PMID: 36978983 PMCID: PMC10044870 DOI: 10.3390/antiox12030735] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/19/2023] Open
Abstract
Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.
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Affiliation(s)
- Somayyeh Ghareghomi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
| | - Faezeh Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
| | - Mehran Habibi-Rezaei
- School of Biology, College of Science, University of Tehran, Tehran 1417466191, Iran
- Center of Excellence in NanoBiomedicine, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
| | - Ali Khatibi
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran 1993893973, Iran;
| | - Jun Hong
- School of Life Sciences, Henan University, Kaifeng 475000, China;
| | - Ali A. Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (F.M.-M.)
- UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (L.S.); (M.H.-R.); (A.A.M.-M.); Tel.: +39-06-4991-2481 (L.S.); +98-21-6111-3214 (M.H.-R.); +98-21-6640-3957 (A.A.M.-M.); Fax: +39-06-4991-2481 (L.S.); +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680(A.A.M.-M.)
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29
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Weiss-Sadan T, Ge M, Hayashi M, Gohar M, Yao CH, de Groot A, Harry S, Carlin A, Fischer H, Shi L, Wei TY, Adelmann CH, Wolf K, Vornbäumen T, Dürr BR, Takahashi M, Richter M, Zhang J, Yang TY, Vijay V, Fisher DE, Hata AN, Haigis MC, Mostoslavsky R, Bardeesy N, Papagiannakopoulos T, Bar-Peled L. NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer. Cell Metab 2023; 35:487-503.e7. [PMID: 36841242 PMCID: PMC9998367 DOI: 10.1016/j.cmet.2023.01.012] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/15/2022] [Accepted: 01/26/2023] [Indexed: 02/27/2023]
Abstract
Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
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Affiliation(s)
- Tommy Weiss-Sadan
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Maolin Ge
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
| | - Makiko Hayashi
- Department of Pathology, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Laura and Isaac Pelmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
| | - Magdy Gohar
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Cong-Hui Yao
- Department of Cell Biology, Blavatnik Institute Harvard Medical School, Boston, MA 02115, USA
| | - Adriaan de Groot
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Stefan Harry
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Alexander Carlin
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Hannah Fischer
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lei Shi
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ting-Yu Wei
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Charles H Adelmann
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Konstantin Wolf
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Tristan Vornbäumen
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Benedikt R Dürr
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mariko Takahashi
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Marianne Richter
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Junbing Zhang
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Tzu-Yi Yang
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Vindhya Vijay
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA
| | - David E Fisher
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Aaron N Hata
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute Harvard Medical School, Boston, MA 02115, USA
| | - Raul Mostoslavsky
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Nabeel Bardeesy
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Thales Papagiannakopoulos
- Department of Pathology, New York University Grossman School of Medicine, 550 First Avenue, New York, NY 10016, USA; Laura and Isaac Pelmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
| | - Liron Bar-Peled
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
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30
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Caligiuri I, Vincenzo C, Asano T, Kumar V, Rizzolio F. The metabolic crosstalk between PIN1 and the tumour microenvironment. Semin Cancer Biol 2023; 91:143-157. [PMID: 36871635 DOI: 10.1016/j.semcancer.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/06/2023]
Abstract
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a member of a family of peptidyl-prolyl isomerases that specifically recognizes and binds phosphoproteins, catalyzing the rapid cis-trans isomerization of phosphorylated serine/threonine-proline motifs, which leads to changes in the structures and activities of the targeted proteins. Through this complex mechanism, PIN1 regulates many hallmarks of cancer including cell autonomous metabolism and the crosstalk with the cellular microenvironment. Many studies showed that PIN1 is largely overexpressed in cancer turning on a set of oncogenes and abrogating the function of tumor suppressor genes. Among these targets, recent evidence demonstrated that PIN1 is involved in lipid and glucose metabolism and accordingly, in the Warburg effect, a characteristic of tumor cells. As an orchestra master, PIN1 finely tunes the signaling pathways allowing cancer cells to adapt and take advantage from a poorly organized tumor microenvironment. In this review, we highlight the trilogy among PIN1, the tumor microenvironment and the metabolic program rewiring.
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Affiliation(s)
- Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Canzonieri Vincenzo
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Tomochiro Asano
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Vinit Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India.
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30123 Venezia, Italy.
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31
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Romo-González M, Ijurko C, Alonso MT, Gómez de Cedrón M, Ramirez de Molina A, Soriano ME, Hernández-Hernández Á. NOX2 and NOX4 control mitochondrial function in chronic myeloid leukaemia. Free Radic Biol Med 2023; 198:92-108. [PMID: 36764627 DOI: 10.1016/j.freeradbiomed.2023.02.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/31/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023]
Abstract
Cancer cells are characterised by an elevated metabolic plasticity and enhanced production of reactive oxygen species (ROS), two features acknowledged as hallmarks in cancer, with a high translational potential to the therapeutic setting. These aspects, that have been traditionally studied separately, are in fact intimately intermingled. As part of their transforming activity, some oncogenes stimulate rewiring of metabolic processes, whilst simultaneously promoting increased production of intracellular ROS. In this scenario the latest discoveries suggest the relevance of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to connect ROS production and metabolic control. Here we have analysed the relevance of NOX2 and NOX4 in the regulation of metabolism in chronic myeloid leukaemia (CML), a neoplasia driven by the expression of the breakpoint cluster region-Abelson fusion oncogene (BCR-ABL). Silencing of NOX2 enhances glycolysis and oxidative phosphorylation rates, together with an enhanced production of mitochondrial ROS and a decrease in mitochondrial DNA copy number, which reflects mitochondrial dysfunction. NOX4 expression was upregulated upon NOX2 silencing, and this was required to alter mitochondrial function. Our results support the relevance of NOX2 to regulate metabolism-related signalling pathways downstream of BCR-ABL. Overall we show that NOX2, through the regulation of NOX4 expression, controls metabolism and mitochondrial function in CML cells. This notion was confirmed by transcriptomic analyses, that strongly relate both NOX isoforms with metabolism regulation in CML.
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Affiliation(s)
- Marta Romo-González
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, 37007, Spain; IBSAL (Instituto de Investigación Biomédica de Salamanca), Salamanca, 37007, Spain
| | - Carla Ijurko
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, 37007, Spain; IBSAL (Instituto de Investigación Biomédica de Salamanca), Salamanca, 37007, Spain
| | - María Teresa Alonso
- Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, 47003, Spain
| | | | | | | | - Ángel Hernández-Hernández
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, 37007, Spain; IBSAL (Instituto de Investigación Biomédica de Salamanca), Salamanca, 37007, Spain.
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32
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Ding Y, Pan Q, Gao W, Pu Y, Luo K, He B. Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy. Biomater Sci 2023; 11:1182-1214. [PMID: 36606593 DOI: 10.1039/d2bm01833k] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H2O2, ˙OH, 1O2, and ˙O2- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.
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Affiliation(s)
- Yuanyuan Ding
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Qingqing Pan
- School of Preclinical Medicine, Chengdu University, Chengdu 610106, China
| | - Wenxia Gao
- College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325027, China
| | - Yuji Pu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
| | - Kui Luo
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Functional and molecular imaging Key Laboratory of Sichuan Province, Sichuan University, Chengdu 610041, China
| | - Bin He
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
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33
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Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell 2023; 186:528-542.e14. [PMID: 36681079 DOI: 10.1016/j.cell.2022.12.036] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 11/08/2022] [Accepted: 12/20/2022] [Indexed: 01/22/2023]
Abstract
Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/CCdh1 and promote mitotic bypass. Cyclin E expression suppresses p53-dependent senescence after mitotic bypass, allowing cells to complete endoreduplication. Our results indicate that p53 can contribute to cancer evolution through the promotion of WGD.
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34
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Hatami H, Sajedi A, Mir SM, Memar MY. Importance of lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) in cancer cells. Health Sci Rep 2023; 6:e996. [PMID: 36570342 PMCID: PMC9768844 DOI: 10.1002/hsr2.996] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/28/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
Background In most regions, cancer ranks the second most frequent cause of death following cardiovascular disorders. Aim In this article, we review the various aspects of glycolysis with a focus on types of MCTs and the importance of lactate in cancer cells. Results and Discussion Metabolic changes are one of the first and most important alterations in cancer cells. Cancer cells use different pathways to survive, energy generation, growth, and proliferation compared to normal cells. The increase in glycolysis, which produces substances such as lactate and pyruvate, has an important role in metastases and invasion of cancer cells. Two important cellular proteins that play a role in the production and transport of lactate include lactate dehydrogenase and monocarboxylate transporters (MCTs). These molecules by their various isoforms and different tissue distribution help to escape the immune system and expansion of cancer cells under different conditions.
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Affiliation(s)
- Hamed Hatami
- Department of Immunology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
| | - Atefe Sajedi
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
| | - Seyed Mostafa Mir
- Metabolic Disorders Research CenterGolestan University of Medical SciencesGorganIran
- Department of Clinical Biochemistry, Faculty of MedicineGolestan University of Medical SciencesGorganIran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research CenterTabriz University of Medical SciencesTabrizIran
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35
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Tuli HS, Kaur J, Vashishth K, Sak K, Sharma U, Choudhary R, Behl T, Singh T, Sharma S, Saini AK, Dhama K, Varol M, Sethi G. Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis. Arch Toxicol 2023; 97:103-120. [PMID: 36443493 DOI: 10.1007/s00204-022-03421-z] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/14/2022] [Indexed: 11/29/2022]
Abstract
ROS include hydroxyl radicals (HO.), superoxide (O2..), and hydrogen peroxide (H2O2). ROS are typically produced under physiological conditions and play crucial roles in living organisms. It is known that ROS, which are created spontaneously by cells through aerobic metabolism in mitochondria, can have either a beneficial or detrimental influence on biological systems. Moderate levels of ROS can cause oxidative damage to proteins, DNA and lipids, which can aid in the pathogenesis of many disorders, including cancer. However, excessive concentrations of ROS can initiate programmed cell death in cancer. Presently, a variety of chemotherapeutic drugs and herbal agents are being investigated to induce ROS-mediated cell death in cancer. Therefore, preserving ROS homeostasis is essential for ensuring normal cell development and survival. On account of a significant association of ROS levels at various concentrations with carcinogenesis in a number of malignancies, further studies are needed to determine the underlying molecular mechanisms and develop the possibilities for intervening in these processes.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, 133207, India
| | - Jagjit Kaur
- Graduate School of Biomedical Engineering, Faculty of Engineering, The University of New South Wales, Sydney, 2052, Australia
| | - Kanupriya Vashishth
- Advance Cardiac Centre Department of Cardiology, PGIMER, Chandigarh, 160012, India
| | | | - Ujjawal Sharma
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, 133207, India
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India
| | - Renuka Choudhary
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, 133207, India
| | - Tapan Behl
- Department of Pharmacology, School of Health Sciences & Technology (SoHST), University of Petroleum and Energy Studies, Bidholi, Dehradun, Uttarakhand, 248007, India
| | - Tejveer Singh
- Translanatal Oncology Laboratory, Department of Zoology, Hansraj College, Delhi University, New Delhi, 110007, India
| | - Sheetu Sharma
- Department of Pharmacovigilace and Clinical Research, Chitkara University, Rajpura, 140401, India
| | - Adesh K Saini
- Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, 133207, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Uttar Pradesh, India
| | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Mugla Sitki Kocman University, Mugla, 48000, Turkey
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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Gothland A, Jary A, Grange P, Leducq V, Beauvais-Remigereau L, Dupin N, Marcelin AG, Calvez V. Harnessing Redox Disruption to Treat Human Herpesvirus 8 (HHV-8) Related Malignancies. Antioxidants (Basel) 2022; 12:antiox12010084. [PMID: 36670946 PMCID: PMC9854560 DOI: 10.3390/antiox12010084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
Reprogrammed metabolism is regarded as a hallmark of cancer and offers a selective advantage to tumor cells during carcinogenesis. The redox equilibrium is necessary for growth, spread and the antioxidant pathways are boosted following Reactive Oxygen Species (ROS) production to prevent cell damage in tumor cells. Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi sarcoma KS and primary effusion lymphoma (PEL), is an oncogenic virus that disrupts cell survival-related molecular signaling pathways leading to immune host evasion, cells growths, angiogenesis and inflammatory tumor-environment. We recently reported that primaquine diphosphate causes cell death by apoptosis in HHV-8 infected PEL cell lines in vivo and exhibits therapeutic anti-tumor activity in mice models and advanced KS. Our findings also suggest that the primaquine-induced apoptosis in PEL cells is mostly influenced by ROS production and targeting the redox balance could be a new approach to treat HHV-8 related diseases. In this review, we summarized the knowledge about the influence of ROS in cancer development; more specifically, the proof of evidence from our work and from the literature that redox pathways are important for the development of HHV-8 pathologies.
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Affiliation(s)
- Adélie Gothland
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Department of Virology, Hôpital Pitié-Salpêtrière, Sorbonne Université, 75013 Paris, France
| | - Aude Jary
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Department of Virology, Hôpital Pitié-Salpêtrière, Sorbonne Université, 75013 Paris, France
- Correspondence: (A.J.); (V.C.); Tel.: +33-1-42-17-74-01 (A.J.)
| | - Philippe Grange
- Cutaneous Biology Lab, INSERM U1016, UMR8104, Institut Cochin, Université de Paris, 24 Rue du Faubourg St Jacques, 75014 Paris, France
- Department of Dermatology, CeGGID et CNR IST Bactériennes, Hôpital Cochin Site Port Royale, AP-HP, Groupe Hospitalier Paris Centre Cochin-Hôtel Dieu-Broca, 123 Boulevard de Port Royal, 75014 Paris, France
| | - Valentin Leducq
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Department of Virology, Hôpital Pitié-Salpêtrière, Sorbonne Université, 75013 Paris, France
| | | | - Nicolas Dupin
- Cutaneous Biology Lab, INSERM U1016, UMR8104, Institut Cochin, Université de Paris, 24 Rue du Faubourg St Jacques, 75014 Paris, France
- Department of Dermatology, CeGGID et CNR IST Bactériennes, Hôpital Cochin Site Port Royale, AP-HP, Groupe Hospitalier Paris Centre Cochin-Hôtel Dieu-Broca, 123 Boulevard de Port Royal, 75014 Paris, France
| | - Anne-Geneviève Marcelin
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Department of Virology, Hôpital Pitié-Salpêtrière, Sorbonne Université, 75013 Paris, France
| | - Vincent Calvez
- INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), AP-HP, Department of Virology, Hôpital Pitié-Salpêtrière, Sorbonne Université, 75013 Paris, France
- Correspondence: (A.J.); (V.C.); Tel.: +33-1-42-17-74-01 (A.J.)
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Branicky R, Wang Y, Khaki A, Liu JL, Kramer-Drauberg M, Hekimi S. Stimulation of RAS-dependent ROS signaling extends longevity by modulating a developmental program of global gene expression. SCIENCE ADVANCES 2022; 8:eadc9851. [PMID: 36449615 PMCID: PMC9710873 DOI: 10.1126/sciadv.adc9851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 10/14/2022] [Indexed: 06/17/2023]
Abstract
We show that elevation of mitochondrial superoxide generation increases Caenorhabditis elegans life span by enhancing a RAS-dependent ROS (reactive oxygen species) signaling pathway (RDRS) that controls the expression of half of the genome as well as animal composition and physiology. RDRS stimulation mimics a program of change in gene expression that is normally observed at the end of postembryonic development. We further show that RDRS is regulated by negative feedback from the superoxide dismutase 1 (SOD-1)-dependent conversion of superoxide into cytoplasmic hydrogen peroxide, which, in turn, acts on a redox-sensitive cysteine (C118) of RAS. Preventing C118 oxidation by replacement with serine, or mimicking oxidation by replacement with aspartic acid, leads to opposite changes in the expression of the same large set of genes that is affected when RDRS is stimulated by mitochondrial superoxide. The identities of these genes suggest that stimulation of the pathway extends life span by boosting turnover and repair while moderating damage from metabolic activity.
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38
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Li X, He M, Zhou Q, Dutta D, Lu N, Li S, Ge Z. Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:50601-50615. [PMID: 36335599 DOI: 10.1021/acsami.2c15406] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The unique tumor microenvironment (TME) characteristic of severe hypoxia, overexpressed intracellular glutathione (GSH), and elevated hydrogen peroxide (H2O2) concentration limit the anticancer effect by monotherapy. In this report, glucose oxidase (GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers containing poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing methacrylate polymeric block, which are termed as GOx@PCoS. After intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS deplete GSH by Co3+ ions. GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance •OH-based chemodynamic therapy (CDT) through the Fenton-like reaction under the catalysis of Co2+. Moreover, Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser irradiation, GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency (45.06%) and generation capacity of the toxic superoxide anion (•O2-) for photothermal therapy (PTT) and photodynamic therapy (PDT). The synergetic antitumor effects can be realized by GSH depletion, starvation, and combined CDT, PTT, and PDT with enhanced efficacy. Notably, GOx@PCoS can also be used as a magnetic resonance imaging (MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS show great potentials to effectively modulate TME and perform synergistic multimodal therapy.
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Affiliation(s)
- Xiang Li
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026Anhui, China
| | - Mei He
- School of Materials Science and Engineering, Anhui University, Hefei230601, P.R. China
| | - Qinghao Zhou
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026Anhui, China
| | - Debabrata Dutta
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026Anhui, China
| | - Nannan Lu
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230001Anhui, China
| | - Shikuo Li
- School of Materials Science and Engineering, Anhui University, Hefei230601, P.R. China
| | - Zhishen Ge
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, 230026Anhui, China
- School of Chemistry, Xi'an Jiaotong University, Xi'an, Shaanxi710049, China
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39
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Vickridge E, Faraco CCF, Tehrani PS, Ramdzan ZM, Djerir B, Rahimian H, Leduy L, Maréchal A, Gingras AC, Nepveu A. The DNA repair function of BCL11A suppresses senescence and promotes continued proliferation of triple-negative breast cancer cells. NAR Cancer 2022; 4:zcac028. [PMID: 36186110 PMCID: PMC9516615 DOI: 10.1093/narcan/zcac028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/08/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
We identified the BCL11A protein in a proximity-dependent biotinylation screen performed with the DNA glycosylase NTHL1. In vitro, DNA repair assays demonstrate that both BCL11A and a small recombinant BCL11A160-520 protein that is devoid of DNA binding and transcription regulatory domains can stimulate the enzymatic activities of two base excision repair enzymes: NTHL1 and DNA Pol β. Increased DNA repair efficiency, in particular of the base excision repair pathway, is essential for many cancer cells to proliferate in the presence of elevated reactive oxygen species (ROS) produced by cancer-associated metabolic changes. BCL11A is highly expressed in triple-negative breast cancers (TNBC) where its knockdown was reported to reduce clonogenicity and cause tumour regression. We show that BCL11A knockdown in TNBC cells delays repair of oxidative DNA damage, increases the number of oxidized bases and abasic sites in genomic DNA, slows down proliferation and induces cellular senescence. These phenotypes are rescued by ectopic expression of the short BCL11A160-520 protein. We further show that the BCL11A160-520 protein accelerates the repair of oxidative DNA damage and cooperates with RAS in cell transformation assays, thereby enabling cells to avoid senescence and continue to proliferate in the presence of high ROS levels.
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Affiliation(s)
- Elise Vickridge
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Camila C F Faraco
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Payman S Tehrani
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Zubaidah M Ramdzan
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Billel Djerir
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - Hedyeh Rahimian
- Department of Biochemistry, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Lam Leduy
- Goodman Cancer Institute, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Alexandre Maréchal
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Alain Nepveu
- To whom correspondence should be addressed. Tel: +1 514 398 5839; Fax: +1 514 398 6769;
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Li X, Zhou Q, Japir AAWMM, Dutta D, Lu N, Ge Z. Protein-Delivering Nanocomplexes with Fenton Reaction-Triggered Cargo Release to Boost Cancer Immunotherapy. ACS NANO 2022; 16:14982-14999. [PMID: 36017992 DOI: 10.1021/acsnano.2c06026] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG), which was followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer, POEGMA-b-PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.
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Affiliation(s)
- Xiang Li
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Qinghao Zhou
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Abd Al-Wali Mohammed M Japir
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Debabrata Dutta
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Nannan Lu
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Zhishen Ge
- CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
- School of Chemistry, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
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41
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Pathophysiology of Ischemic Stroke: Noncoding RNA Role in Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5815843. [PMID: 36132228 PMCID: PMC9484962 DOI: 10.1155/2022/5815843] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/12/2022] [Accepted: 08/20/2022] [Indexed: 11/29/2022]
Abstract
Stroke is a neurological disease that causes significant disability and death worldwide. Ischemic stroke accounts for 75% of all strokes. The pathophysiological processes underlying ischemic stroke include oxidative stress, the toxicity of excitatory amino acids, ion disorder, enhanced apoptosis, and inflammation. Noncoding RNAs (ncRNAs) may have a vital role in regulating the pathophysiological processes of ischemic stroke, as confirmed by the altered expression of ncRNAs in blood samples from acute ischemic stroke patients, animal models, and oxygen-glucose-deprived (OGD) cell models. Due to specific changes in expression, ncRNAs can potentially be biomarkers for the diagnosis, treatment, and prognosis of ischemic stroke. As an important brain cell component, glial cells mediate the occurrence and progression of oxidative stress after ischemic stroke, and ncRNAs are an irreplaceable part of this mechanism. This review highlights the impact of ncRNAs in the oxidative stress process of ischemic stroke. It focuses on specific ncRNAs that underlie the pathophysiology of ischemic stroke and have potential as diagnostic biomarkers and therapeutic targets.
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42
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Bartolacci C, Andreani C, Vale G, Berto S, Melegari M, Crouch AC, Baluya DL, Kemble G, Hodges K, Starrett J, Politi K, Starnes SL, Lorenzini D, Raso MG, Solis Soto LM, Behrens C, Kadara H, Gao B, Wistuba II, Minna JD, McDonald JG, Scaglioni PP. Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer. Nat Commun 2022; 13:4327. [PMID: 35882862 PMCID: PMC9325712 DOI: 10.1038/s41467-022-31963-4] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/06/2022] [Indexed: 12/22/2022] Open
Abstract
Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either FASN or the Lands cycle in KMLC, promotes ferroptosis, a reactive oxygen species (ROS)- and iron-dependent cell death, characterized by the intracellular accumulation of oxidation-prone PC. Our work indicates that KM dictates a dependency on newly synthesized FA to escape ferroptosis, establishing a targetable vulnerability in KMLC.
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Affiliation(s)
- Caterina Bartolacci
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA
| | - Cristina Andreani
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA
| | - Gonçalo Vale
- Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Stefano Berto
- Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Margherita Melegari
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA
| | - Anna Colleen Crouch
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dodge L Baluya
- Tissue Imaging and Proteomics Laboratory, Washington State University, Pullman, WA, 99164, USA
| | | | - Kurt Hodges
- Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA
| | | | - Katerina Politi
- Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA
| | - Sandra L Starnes
- Department of Surgery, Division of Thoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA
| | - Daniele Lorenzini
- Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, via Venezian 1, 20133, Milan, Italy
| | - Maria Gabriela Raso
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Luisa M Solis Soto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carmen Behrens
- Department of Thoracic H&N Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Humam Kadara
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Boning Gao
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John D Minna
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jeffrey G McDonald
- Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Pier Paolo Scaglioni
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45219, USA.
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Kirova DG, Judasova K, Vorhauser J, Zerjatke T, Leung JK, Glauche I, Mansfeld J. A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase. Dev Cell 2022; 57:1712-1727.e9. [PMID: 35809563 PMCID: PMC9616724 DOI: 10.1016/j.devcel.2022.06.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/13/2022] [Accepted: 06/14/2022] [Indexed: 02/08/2023]
Abstract
Reactive oxygen species (ROS) at the right concentration promote cell proliferation in cell culture, stem cells, and model organisms. However, the mystery of how ROS signaling is coordinated with cell cycle progression and integrated into the cell cycle control machinery on the molecular level remains unsolved. Here, we report increasing levels of mitochondrial ROS during the cell cycle in human cell lines that target cyclin-dependent kinase 2 (CDK2). Chemical and metabolic interferences with ROS production decrease T-loop phosphorylation on CDK2 and so impede its full activation and thus its efficient DNA replication. ROS regulate CDK2 activity through the oxidation of a conserved cysteine residue near the T-loop, which prevents the binding of the T-loop phosphatase KAP. Together, our data reveal how mitochondrial metabolism is coupled with DNA replication and cell cycle progression via ROS, thereby demonstrating how KAP activity toward CDKs can be cell cycle regulated.
Mitochondrial ROS drive cell cycle progression and proliferation Cyclin-dependent kinase 2 (CDK2) is increasingly oxidized during the cell cycle The oxidation state of a conserved cysteine on CDK2 regulates KAP binding CDK2 oxidation promotes T-loop phosphorylation and DNA replication
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Affiliation(s)
| | - Kristyna Judasova
- Cell Cycle, Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany
| | - Julia Vorhauser
- Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK; Cell Cycle, Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany
| | - Thomas Zerjatke
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Jacky Kieran Leung
- Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK
| | - Ingmar Glauche
- Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Jörg Mansfeld
- Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK; Cell Cycle, Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
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Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison. Front Immunol 2022; 13:889875. [PMID: 35757686 PMCID: PMC9218220 DOI: 10.3389/fimmu.2022.889875] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/10/2022] [Indexed: 11/24/2022] Open
Abstract
Reactive oxygen species (ROS), previously considered toxic by-products of aerobic metabolism, are increasingly recognized as regulators of cellular signaling. Keeping ROS levels low is essential to safeguard the self-renewal capacity of hematopoietic stem cells (HSC). HSC reside in a hypoxic environment and have been shown to be highly dependent on the glycolytic pathway to meet their energy requirements. However, when the differentiation machinery is activated, there is an essential enhancement of ROS together with a metabolic shift toward oxidative metabolism. Initiating and sustaining leukemia depend on the activity of leukemic stem cells (LSC). LSC also show low ROS levels, but unlike HSC, LSC rely on oxygen to meet their metabolic energetic requirements through mitochondrial respiration. In contrast, leukemic blasts show high ROS levels and great metabolic plasticity, both of which seem to sustain their invasiveness. Oxidative stress and metabolism rewiring are recognized as hallmarks of cancer that are intimately intermingled. Here we present a detailed overview of these two features, sustained at different levels, that support a two-way relationship in leukemia. Modifying ROS levels and targeting metabolism are interesting therapeutic approaches. Therefore, we provide the most recent evidence on the modulation of oxidative stress and metabolism as a suitable anti-leukemic approach.
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Affiliation(s)
- Marta Romo-González
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain
| | - Carla Ijurko
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain
| | - Ángel Hernández-Hernández
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain
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45
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Zhu H, Chan KT, Huang X, Cerra C, Blake S, Trigos AS, Anderson D, Creek DJ, De Souza DP, Wang X, Fu C, Jana M, Sanij E, Pearson RB, Kang J. Cystathionine-β-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation. eLife 2022; 11:e71929. [PMID: 35758651 PMCID: PMC9236611 DOI: 10.7554/elife.71929] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 06/07/2022] [Indexed: 12/30/2022] Open
Abstract
Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.
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Affiliation(s)
- Haoran Zhu
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
| | - Keefe T Chan
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
| | - Xinran Huang
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
| | - Carmelo Cerra
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
| | - Shaun Blake
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
| | - Anna S Trigos
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
| | - Dovile Anderson
- Monash Institute of Pharmaceutical SciencesVictoriaAustralia
| | - Darren J Creek
- Monash Institute of Pharmaceutical SciencesVictoriaAustralia
| | - David P De Souza
- Metabolomics Australia, Bio21 Molecular Science and Biotechnology InstituteVictoriaAustralia
| | - Xi Wang
- Department of Oncology, The People’s Liberation Army No. 903rd HospitalHangzhouChina
| | - Caiyun Fu
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech UniversityHangzhouChina
| | - Metta Jana
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
| | - Elaine Sanij
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
- St Vincent’s Institute of Medical ResearchMelbourneAustralia
- Department of Clinical Pathology, University of MelbourneMelbourneAustralia
- Department of Biochemistry and Molecular Biology, Monash UniversityMelbourneAustralia
- Department of Medicine, St Vincent’s Hospital, University of MelbourneMelbourneAustralia
| | - Richard B Pearson
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
- Department of Biochemistry and Molecular Biology, Monash UniversityMelbourneAustralia
- Department of Biochemistry and Molecular Biology, University of MelbourneMelbourneAustralia
| | - Jian Kang
- Division of Cancer Research, Peter MacCallum Cancer CentreMelbourneAustralia
- Sir Peter MacCallum Department of Oncology, University of MelbourneMelbourneAustralia
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Vickridge E, Faraco CCF, Nepveu A. Base excision repair accessory factors in senescence avoidance and resistance to treatments. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:703-720. [PMID: 36176767 PMCID: PMC9511810 DOI: 10.20517/cdr.2022.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 06/16/2023]
Abstract
Cancer cells, in which the RAS and PI3K pathways are activated, produce high levels of reactive oxygen species (ROS), which cause oxidative DNA damage and ultimately cellular senescence. This process has been documented in tissue culture, mouse models, and human pre-cancerous lesions. In this context, cellular senescence functions as a tumour suppressor mechanism. Some rare cancer cells, however, manage to adapt to avoid senescence and continue to proliferate. One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor. In this review, we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS: the increased activity of the base excision repair (BER) pathway, achieved through the enhanced expression of BER enzymes and DNA repair accessory factors. These proteins, exemplified here by the CUT domain proteins CUX1, CUX2, and SATB1, stimulate the activity of BER enzymes. The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels. As a by-product of this adaptation, these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation, temozolomide, and cisplatin. Moreover, considering the intrinsic error rate associated with DNA repair and translesion synthesis, the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population, thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance, a major obstacle to clinical treatment.
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Affiliation(s)
- Elise Vickridge
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- These authors contributed equally to this work
| | - Camila C. F. Faraco
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- These authors contributed equally to this work
| | - Alain Nepveu
- Goodman Cancer Institute, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Departments of Biochemistry, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Medicine, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
- Oncology, McGill University, 1160 Pine avenue West, Montreal, Québec H3A 1A3, Canada
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47
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Wu Z, Pan T, Lin D, Xia W, Shan J, Cheng R, Yang M, Hu X, Nan K, Qi L. Biocompatible tumor-targeted GQDs nanocatalyst for chemodynamic tumor therapy. J Mater Chem B 2022; 10:3567-3576. [PMID: 35420085 DOI: 10.1039/d1tb02734d] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To deal with the complex tumor microenvironment (TME), chemodynamic therapy (CDT) has been developed, which uses nanocatalysts simulating peroxidase to convert high concentration hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH) in situ and effectively kills tumor cells. Due to the low catalytic activity of traditional nanocatalysts, the present CDT treatment has to be combined with other anti-tumor therapies, which increases the complexity and uncertainty of the treatment. Thus, developing new nanocatalysts with stable and high enzymatic activity is the key point to CDT treatment. Graphene quantum dots (GQDs) are important metal-free catalysts with intrinsic peroxidase-like activity due to their excellent electron transport performance. Here, we prepare a nitrogen-doped GQD (NGOD) nanocatalyst, which displays much higher peroxidase activity than known metal nanocatalysts. The NGQD nanocatalyst is further grafted with RGDS peptide-modified polyethylene glycol (PEG), which guides the nanocatalyst to the tumor area and increases its circulation time in blood. The as-produced RGDS-PEG@NG nanocatalyst displays stable and high peroxidase activity, which achieves the conversion of H2O2 → ˙OH in the TME. Through an in vivo study it has been observed that RGDS-PEG@NGs obviously inhibit tumor growth without combining with other treatment methods and show excellent biocompatibility, which provides a unique idea for the application of GQDs in CDT.
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Affiliation(s)
- Zixia Wu
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Tonghe Pan
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Deqing Lin
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Weibo Xia
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Jia Shan
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Rumei Cheng
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Mei Yang
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Xuting Hu
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Kaihui Nan
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
| | - Lei Qi
- State key Laboratory of Ophthalmology, Optometry and Visual Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital Wenzhou Medical University 270 Xueyuanxi Road, Wenzhou 325027, China.
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48
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ROS-Related miRNAs Regulate Immune Response and Chemoradiotherapy Sensitivity in Hepatocellular Carcinoma by Comprehensive Analysis and Experiment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4713518. [PMID: 35585886 PMCID: PMC9110211 DOI: 10.1155/2022/4713518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/09/2022] [Indexed: 11/28/2022]
Abstract
Reactive oxygen species (ROS) plays an essential role in the development of cancer. Here, we chose ROS-related miRNAs for consensus clustering analysis and ROS score construction. We find that ROS is extremely associated with prognosis, tumor immune microenvironment (TIME), gene mutations, N6-methyladenosine (m6A) methylation, and chemotherapy sensitivity in hepatocellular carcinoma (HCC). Mechanistically, ROS may affect the prognosis of HCC patients in numerous ways. Moreover, miR-210-3p and miR-106a-5p significantly increased the ROS level and stagnated cell cycle at G2/M in HCC; the results were more obvious in cells after ionizing radiation (IR). Finally, the two miRNAs suppressed cell proliferation, migration, and invasion and promoted apoptosis in huh7 and smmc7721 cells. It indicated that ROS might affect the prognosis of HCC patients through immune response and increase the sensitivity of HCC patients to radiotherapy and chemotherapy.
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49
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Krstic J, Schindlmaier K, Prokesch A. Combination strategies to target metabolic flexibility in cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 373:159-197. [PMID: 36283766 DOI: 10.1016/bs.ircmb.2022.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Therapeutically interfering with metabolic pathways has great merit to curtail tumor growth because the demand for copious amounts of energy for growth-supporting biomass production is common to all cancer entities. A major impediment to a straight implementation of metabolic cancer therapy is the metabolic flexibility and plasticity of cancer cells (and their microenvironment) resulting in therapy resistance and evasion. Metabolic combination therapies, therefore, are promising as they are designed to target several energetic routes simultaneously and thereby diminish the availability of alternative substrates. Thus, dietary restrictions, specific nutrient limitations, and/or pharmacological interventions impinging on metabolic pathways can be combined to improve cancer treatment efficacy, to overcome therapy resistance, or even act as a preventive measure. Here, we review the most recent developments in metabolic combination therapies particularly highlighting in vivo reports of synergistic effects and available clinical data. We close with identifying the challenges of the field (metabolic tumor heterogeneity, immune cell interactions, inter-patient variabilities) and suggest a "metabo-typing" strategy to tailor evidence-based metabolic combination therapies to the energetic requirements of the tumors and the patient's nutritional habits and status.
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Affiliation(s)
- Jelena Krstic
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Graz, Austria
| | - Katharina Schindlmaier
- Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Prokesch
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
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50
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Hasan A, Rizvi SF, Parveen S, Pathak N, Nazir A, Mir SS. Crosstalk Between ROS and Autophagy in Tumorigenesis: Understanding the Multifaceted Paradox. Front Oncol 2022; 12:852424. [PMID: 35359388 PMCID: PMC8960719 DOI: 10.3389/fonc.2022.852424] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022] Open
Abstract
Cancer formation is a highly regulated and complex process, largely dependent on its microenvironment. This complexity highlights the need for developing novel target-based therapies depending on cancer phenotype and genotype. Autophagy, a catabolic process, removes damaged and defective cellular materials through lysosomes. It is activated in response to stress conditions such as nutrient deprivation, hypoxia, and oxidative stress. Oxidative stress is induced by excess reactive oxygen species (ROS) that are multifaceted molecules that drive several pathophysiological conditions, including cancer. Moreover, autophagy also plays a dual role, initially inhibiting tumor formation but promoting tumor progression during advanced stages. Mounting evidence has suggested an intricate crosstalk between autophagy and ROS where they can either suppress cancer formation or promote disease etiology. This review highlights the regulatory roles of autophagy and ROS from tumor induction to metastasis. We also discuss the therapeutic strategies that have been devised so far to combat cancer. Based on the review, we finally present some gap areas that could be targeted and may provide a basis for cancer suppression.
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Affiliation(s)
- Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow, India.,Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
| | - Suroor Fatima Rizvi
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow, India.,Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
| | - Sana Parveen
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow, India.,Department of Biosciences, Faculty of Science, Integral University, Lucknow, India
| | - Neelam Pathak
- Department of Biochemistry, Dr. RML Avadh University, Faizabad, India
| | - Aamir Nazir
- Laboratory of Functional Genomics and Molecular Toxicology, Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow, India.,Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India
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