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Aye HM, Li FJ, He CY. Dynamic composition of stress granules in Trypanosoma brucei. PLoS Pathog 2024; 20:e1012666. [PMID: 39480887 PMCID: PMC11556693 DOI: 10.1371/journal.ppat.1012666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 11/12/2024] [Accepted: 10/14/2024] [Indexed: 11/02/2024] Open
Abstract
Stress granules (SGs) are stress-induced RNA condensates consisting of stalled initiation complexes resulting from translational inhibition. The biochemical composition and function of SGs are highly diverse, and this diversity has been attributed to different stress conditions, signalling pathways involved and specific cell types. Interestingly, mRNA decay components, which are found in ubiquitous cytoplasmic foci known as processing bodies (PB), have also been identified in SG proteomes. A major challenge in current SG studies is to understand the cause of SG diversity, as well as the function of SG under different stress conditions. Trypanosoma brucei is a single-cellular parasite that causes Human African Trypanosomiasis (sleeping sickness). In this study, we showed that by varying the supply of extracellular carbon sources during starvation, cellular ATP levels changed rapidly, resulting in SGs of different compositions and dynamics. We identified a subset of SG components, which dissociated from the SGs in response to cellular ATP depletion. Using expansion microscopy, we observed sub-granular compartmentalization of PB- and SG-components within the stress granules. Our results highlight the importance of cellular ATP in SG composition and dynamics, providing functional insight to SGs formed under different stress conditions.
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Affiliation(s)
- Htay Mon Aye
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Feng-Jun Li
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Cynthia Y. He
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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2
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Zheng C, Yu L, Zhao L, Guo M, Feng M, Li H, Zhou X, Fan Y, Liu L, Ma Z, Jia Y, Li M, Barman I, Yu Z. Label-free Raman spectroscopy reveals tumor microenvironmental changes induced by intermittent fasting for the prevention of breast cancer in animal model. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 317:124387. [PMID: 38704999 DOI: 10.1016/j.saa.2024.124387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 04/06/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024]
Abstract
The development of tools that can provide a holistic picture of the evolution of the tumor microenvironment in response to intermittent fasting on the prevention of breast cancer is highly desirable. Here, we show, for the first time, the use of label-free Raman spectroscopy to reveal biomolecular alterations induced by intermittent fasting in the tumor microenvironment of breast cancer using a dimethyl-benzanthracene induced rat model. To quantify biomolecular alterations in the tumor microenvironment, chemometric analysis of Raman spectra obtained from untreated and treated tumors was performed using multivariate curve resolution-alternative least squares and support vector machines. Raman measurements revealed remarkable and robust differences in lipid, protein, and glycogen content prior to morphological manifestations in a dynamically changing tumor microenvironment, consistent with the proteomic changes observed by quantitative mass spectrometry. Taken together with its non-invasive nature, this research provides prospective evidence for the clinical translation of Raman spectroscopy to identify biomolecular variations in the microenvironment induced by intermittent fasting for the prevention of breast cancer, providing new perspectives on the specific molecular effects in the tumorigenesis of breast cancer.
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Affiliation(s)
- Chao Zheng
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Lixiang Yu
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Linfeng Zhao
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Maolin Guo
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Man Feng
- Department of Pathology, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences), Jinan, Shandong 250031, China
| | - Hui Li
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, China
| | - Xingchen Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan, Shandong 250033, China
| | - Yeye Fan
- School of Mathematics, Shandong University, Jinan, Shandong 250100, China
| | - Liyuan Liu
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Zhongbing Ma
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Yining Jia
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China
| | - Ming Li
- School of Materials Science and Engineering, Central South University, Changsha, Hunan 410083, China
| | - Ishan Barman
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA.
| | - Zhigang Yu
- Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, Shandong 250033, China.
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3
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Amin N, Abbasi IN, Wu F, Shi Z, Sundus J, Badry A, Yuan X, Zhao BX, Pan J, Mi XD, Luo Y, Geng Y, Fang M. The Janus face of HIF-1α in ischemic stroke and the possible associated pathways. Neurochem Int 2024; 177:105747. [PMID: 38657682 DOI: 10.1016/j.neuint.2024.105747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.
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Affiliation(s)
- Nashwa Amin
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Department of Zoology, Faculty of Science, Aswan University, Egypt; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Irum Naz Abbasi
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Wu
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongjie Shi
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Javaria Sundus
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Azhar Badry
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Yuan
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Bing-Xin Zhao
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jie Pan
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Xiao-Dan Mi
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yuhuan Luo
- Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Geng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Marong Fang
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
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Gatti P, Mukherjee P, Talukdar PD, Freppel W, Kanou J, Chatel-chaix L, Chatterji U, Germain M. Extracellular matrix signals promotes actin-dependent mitochondrial elongation and activity.. [DOI: 10.1101/2024.01.22.576703] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
AbstractMitochondria are crucial metabolic organelles that are regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signalling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from the general survival cues generated by the ECM, we used breast cancer-derived spheres (mammospheres) because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity, but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.
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Ahmadpour ST, Orre C, Bertevello PS, Mirebeau-Prunier D, Dumas JF, Desquiret-Dumas V. Breast Cancer Chemoresistance: Insights into the Regulatory Role of lncRNA. Int J Mol Sci 2023; 24:15897. [PMID: 37958880 PMCID: PMC10650504 DOI: 10.3390/ijms242115897] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are a subclass of noncoding RNAs composed of more than 200 nucleotides without the ability to encode functional proteins. Given their involvement in critical cellular processes such as gene expression regulation, transcription, and translation, lncRNAs play a significant role in organism homeostasis. Breast cancer (BC) is the second most common cancer worldwide and evidence has shown a relationship between aberrant lncRNA expression and BC development. One of the main obstacles in BC control is multidrug chemoresistance, which is associated with the deregulation of multiple mechanisms such as efflux transporter activity, mitochondrial metabolism reprogramming, and epigenetic regulation as well as apoptosis and autophagy. Studies have shown the involvement of a large number of lncRNAs in the regulation of such pathways. However, the underlying mechanism is not clearly elucidated. In this review, we present the principal mechanisms associated with BC chemoresistance that can be directly or indirectly regulated by lncRNA, highlighting the importance of lncRNA in controlling BC chemoresistance. Understanding these mechanisms in deep detail may interest the clinical outcome of BC patients and could be used as therapeutic targets to overcome BC therapy resistance.
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Affiliation(s)
- Seyedeh Tayebeh Ahmadpour
- Nutrition, Croissance et Cancer, Inserm, UMR1069, Université de Tours, 37032 Tours, France; (P.S.B.); (J.-F.D.)
| | - Charlotte Orre
- Inserm U1083, UMR CNRS 6214, Angers University, 49933 Angers, France; (C.O.); (D.M.-P.)
| | - Priscila Silvana Bertevello
- Nutrition, Croissance et Cancer, Inserm, UMR1069, Université de Tours, 37032 Tours, France; (P.S.B.); (J.-F.D.)
| | | | - Jean-François Dumas
- Nutrition, Croissance et Cancer, Inserm, UMR1069, Université de Tours, 37032 Tours, France; (P.S.B.); (J.-F.D.)
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Wang Y, Gao S, Xu Y, Tang Z, Liu S. Characterization of starvation response-related genes for predicting prognosis in breast cancer. Cancer Sci 2023; 114:3144-3161. [PMID: 37199031 PMCID: PMC10394156 DOI: 10.1111/cas.15836] [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: 01/19/2023] [Revised: 03/29/2023] [Accepted: 04/23/2023] [Indexed: 05/19/2023] Open
Abstract
Breast cancer (BRCA) cells typically exist in nutrient-deficient microenvironments and quickly adapt to states with fluctuating nutrient levels. The tumor microenvironment of starvation is intensely related to metabolism and the malignant progression of BRCA. However, the potential molecular mechanism has not been thoroughly scrutinized. As a result, this study aimed to dissect the prognostic implications of mRNAs involved in the starvation response and construct a signature for forecasting the outcomes of BRCA. In this research, we investigated how starvation could affect BRCA cells' propensities for invasion and migration. The effects of autophagy and glucose metabolism mediated by starved stimulation were examined through transwell assays, western blot, and the detection of glucose concentration. A starvation response-related gene (SRRG) signature was ultimately generated by integrated analysis. The risk score was recognized as an independent risk indicator. The nomogram and calibration curves revealed that the model had excellent prediction accuracy. Functional enrichment analysis indicated this signature was significantly enriched in metabolic-related pathways and energy stress-related biological processes. Furthermore, phosphorylated protein expression of the model core gene EIF2AK3 increased after the stimulus of starvation, and EIF2AK3 may play an essential role in the progression of BRCA in the starved microenvironment. To sum up, we constructed and validated a novel SRRG signature that could accurately predict outcomes and may be developed as a therapeutic target for the precise treatment of BRCA.
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Affiliation(s)
- Yuan Wang
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Laboratory Research CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Shun Gao
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Laboratory Research CenterThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yingkun Xu
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Zhenrong Tang
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Shengchun Liu
- Department of Breast and Thyroid SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
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Wu Q, Sharma D. Autophagy and Breast Cancer: Connected in Growth, Progression, and Therapy. Cells 2023; 12:1156. [PMID: 37190065 PMCID: PMC10136604 DOI: 10.3390/cells12081156] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Despite an increase in the incidence of breast cancer worldwide, overall prognosis has been consistently improving owing to the development of multiple targeted therapies and novel combination regimens including endocrine therapies, aromatase inhibitors, Her2-targeted therapies, and cdk4/6 inhibitors. Immunotherapy is also being actively examined for some breast cancer subtypes. This overall positive outlook is marred by the development of resistance or reduced efficacy of the drug combinations, but the underlying mechanisms are somewhat unclear. It is interesting to note that cancer cells quickly adapt and evade most therapies by activating autophagy, a catabolic process designed to recycle damaged cellular components and provide energy. In this review, we discuss the role of autophagy and autophagy-associated proteins in breast cancer growth, drug sensitivity, tumor dormancy, stemness, and recurrence. We further explore how autophagy intersects and reduces the efficacy of endocrine therapies, targeted therapies, radiotherapy, chemotherapies as well as immunotherapy via modulating various intermediate proteins, miRs, and lncRNAs. Lastly, the potential application of autophagy inhibitors and bioactive molecules to improve the anticancer effects of drugs by circumventing the cytoprotective autophagy is discussed.
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Affiliation(s)
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287-0013, USA
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Zhang L, Cui T, Wang X. The Interplay Between Autophagy and Regulated Necrosis. Antioxid Redox Signal 2023; 38:550-580. [PMID: 36053716 PMCID: PMC10025850 DOI: 10.1089/ars.2022.0110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022]
Abstract
Significance: Autophagy is critical to cellular homeostasis. Emergence of the concept of regulated necrosis, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial membrane-permeability transition (MPT)-derived necrosis, has revolutionized the research into necrosis. Both altered autophagy and regulated necrosis contribute to major human diseases. Recent studies reveal an intricate interplay between autophagy and regulated necrosis. Understanding the interplay at the molecular level will provide new insights into the pathophysiology of related diseases. Recent Advances: Among the three forms of autophagy, macroautophagy is better studied for its crosstalk with regulated necrosis. Macroautophagy seemingly can either antagonize or promote regulated necrosis, depending upon the form of regulated necrosis, the type of cells or stimuli, and other cellular contexts. This review will critically analyze recent advances in the molecular mechanisms governing the intricate dialogues between macroautophagy and main forms of regulated necrosis. Critical Issues: The dual roles of autophagy, either pro-survival or pro-death characteristics, intricate the mechanistic relationship between autophagy and regulated necrosis at molecular level in various pathological conditions. Meanwhile, key components of regulated necrosis are also involved in the regulation of autophagy, which further complicates the interrelationship. Future Directions: Resolving the controversies over causation between altered autophagy and a specific form of regulated necrosis requires approaches that are more definitive, where rigorous evaluation of autophagic flux and the development of more reliable and specific methods to quantify each form of necrosis will be essential. The relationship between chaperone-mediated autophagy or microautophagy and regulated necrosis remains largely unstudied. Antioxid. Redox Signal. 38, 550-580.
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Affiliation(s)
- Lei Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China
- Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Agricultural University, Changchun, China
| | - Taixing Cui
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina, USA
| | - Xuejun Wang
- Division of Basic Biomedical Sciences, The University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, USA
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9
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Ning B, Liu Y, Huang T, Wei Y. Autophagy and its role in osteosarcoma. Cancer Med 2023; 12:5676-5687. [PMID: 36789748 PMCID: PMC10028045 DOI: 10.1002/cam4.5407] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 10/10/2022] [Accepted: 10/24/2022] [Indexed: 02/16/2023] Open
Abstract
Osteosarcoma (OS) is the most common bone malignancy and preferably occurs in children and adolescents. Despite significant advances in surgery and chemotherapy for OS over the past few years, overall survival rates of OS have reached a bottleneck. Thus, extensive researches aimed at developing new therapeutic targets for OS are urgently needed. Autophagy, a conserved process which allows cells to recycle altered or unused organelles and cellular components, has been proven to play a critical role in multiple biological processes in OS. In this article, we summarized the association between autophagy and proliferation, metastasis, chemotherapy, radiotherapy, and immunotherapy of OS, revealing that autophagy-related genes and pathways could serve as potential targets for OS therapy.
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Affiliation(s)
- Biao Ning
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yixin Liu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Tianhe Huang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yongchang Wei
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Key Laboratory of Tumor Biological Behaviors Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Hubei Cancer Clinical Study Center Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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10
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Giannopoulos S, Bozkus CC, Zografos E, Athanasiou A, Bongiovanni AM, Doulaveris G, Bakoyiannis CN, Theodoropoulos GE, Zografos GC, Witkin SS, Orfanelli T. Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment. Metabolites 2022; 12:metabo12100966. [PMID: 36295867 PMCID: PMC9607060 DOI: 10.3390/metabo12100966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/30/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.
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Affiliation(s)
- Spyridon Giannopoulos
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Cansu Cimen Bozkus
- Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA
| | - Eleni Zografos
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Aikaterini Athanasiou
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Ann Marie Bongiovanni
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Georgios Doulaveris
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Chris N Bakoyiannis
- First Department of Surgery, Division of Vascular Surgery, Laikon General Hospital, National Kapodistrian University of Athens, 15772 Athens, Greece
| | - Georgios E Theodoropoulos
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Georgios C Zografos
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Steven S Witkin
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Theofano Orfanelli
- First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
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11
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Gillson J, Abd El-Aziz YS, Leck LYW, Jansson PJ, Pavlakis N, Samra JS, Mittal A, Sahni S. Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target. Cancers (Basel) 2022; 14:3528. [PMID: 35884592 PMCID: PMC9315706 DOI: 10.3390/cancers14143528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression.
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Affiliation(s)
- Josef Gillson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Nick Pavlakis
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
| | - Jaswinder S. Samra
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
| | - Anubhav Mittal
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Upper GI Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
- School of Medicine, University of Notre Dame, Darlinghurst, Sydney, NSW 2010, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Camperdown, Sydney, NSW 2050, Australia; (J.G.); (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.); (N.P.); (J.S.S.); (A.M.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, Sydney, NSW 2065, Australia
- Australian Pancreatic Centre, St Leonards, Sydney, NSW 2065, Australia
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12
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Yuan M, Yao Y, Wu D, Zhu C, Dong S, Tong X. Pannexin1 inhibits autophagy of cisplatin-resistant testicular cancer cells by mediating ATP release. Cell Cycle 2022; 21:1651-1661. [PMID: 35373707 PMCID: PMC9291690 DOI: 10.1080/15384101.2022.2060655] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Pannexin1 (Panx-1) is a gap junction channel protein that mediates the release of intracellular ATP during autophagy, and thus plays an important role in tumor cell apoptosis and chemo-resistance. However, the role of Panx-1 in cisplatin-resistance of testicular cancer cells remains unclear. We found that cisplatin-resistant I-10 testicular cancer cell lines (I-10/CDDP) autophagy-associated proteins (p62, p-mTOR, mTOR and LC3) exhibited high levels of autophagy in their expression, while LC3-II expression was more significantly in the presence of lysosomal degradation blocked by chloroquine (CQ). Xenograft models using I-10/CDDP cells with knockdown ATG5 and ATG7 were established in mouse models and showed blockade of autophagic flux and inhibition of tumor growth. In addition, inhibition of Panx-1 by carbenoxolone (CBX) and probenecid (PBN), as well as shRNA-mediated knockdown promoted autophagy in the I-10/CDDP cells, which was accompanied by a decrease in the levels of extracellular ATP. In contrast, overexpression of Panx-1 decreased autophagy of I-10/CDDP cells and increased extracellular ATP levels. To further determine the effect of panx-1-mediated ATP release on the autophagy of I-10/CDDP cells, apyrase was used to hydrolyze the extracellular ATP. Apyrase promoted autophagy in I-10/CDDP cells city by decreasing extracellular ATP, regardless of Panx-1 expression. This study demonstrated for the first time that Panx-1-mediated ATP release inhibits autophagy of I-10/CDDP cells, which provides a potential therapeutic strategy for cisplatin-resistant testicular cancer.
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Affiliation(s)
- Min Yuan
- School of Pharmacy, Bengbu Medical College, Bengbu, PR China
| | - Yanxue Yao
- School of Pharmacy, Bengbu Medical College, Bengbu, PR China
| | - Dandan Wu
- State KeyLaboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Xiang, China
| | - Chenlu Zhu
- School of Pharmacy, Bengbu Medical College, Bengbu, PR China
| | - Shuying Dong
- School of Pharmacy, Bengbu Medical College, Bengbu, PR China
| | - Xuhui Tong
- School of Pharmacy, Bengbu Medical College, Bengbu, PR China
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13
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Xu L, Zhang C, Yin H, Gong S, Wu N, Ren Z, Zhang Y. RNA modifications act as regulators of cell death. RNA Biol 2021; 18:2183-2193. [PMID: 34313542 PMCID: PMC8632120 DOI: 10.1080/15476286.2021.1925460] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/14/2022] Open
Abstract
Currently, more than one hundred types of RNA modifications have been found, and many of these modifications are reversible and dynamically regulated. RNA modifications can regulate RNA stability and translation and are thus involved in multiple biological activities. Recently, RNA modifications have been shown to have important roles in the regulation of cell death. Cell death is a critical process that maintains tissue homoeostasis and is regulated by multiple pathways in response to specific stimuli. In this review, we summarize the current understanding of the roles of RNA modifications in cell death mediation and discuss the prospects of such research.Abbreviations: m6A, N6-Methyladenosine; m6Am, N6,2'-O-Dimethyladenosine; m1A, N1-Methyladenosine; m5C, 5-Methylcytosine; hm5C, 5-Hydroxymethylcytosine; Ψ, pseudouridine; A-to-I, adenosine-to- inosine; hnRNPs, heterogeneous nuclear ribonucleoproteins; MOMP, mitochondrial outer membrane permeabilization; DD, death domain; DISC, death-inducing signalling complex; DED, death effector domain; FADD, FAS-associated protein with the death domain; TRADD, TNF receptor-associated protein with death domain; CMA, chaperone- mediated autophagy; PE, phosphatidylethanolamine; AD, alzheimer's disease; AML, acute myeloid leukaemia; miR, microRNA; 6-OHDA, 6-hydroxydopamine hydrochloride; R-2HG, R-2-hydroxyglutarate; IRES, internal ribosome entry site; BMSCs, bone-derived mesenchymal stem cells; NPCs, nucleus pulposus cells; HsCG, human chorionic gonadotropin; snoRNAs, small nucleolar RNAs; ER, endoplasmic reticulum; lncRNAs, long noncoding RNAs; TNM, tumour-node-metastasis.
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Affiliation(s)
- Lei Xu
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chong Zhang
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hang Yin
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Shuai Gong
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Nai Wu
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Zeqiang Ren
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yi Zhang
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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14
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Cardiac Glycosides as Autophagy Modulators. Cells 2021; 10:cells10123341. [PMID: 34943848 PMCID: PMC8699753 DOI: 10.3390/cells10123341] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/26/2022] Open
Abstract
Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.
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15
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Abd El-Aziz YS, Gillson J, Jansson PJ, Sahni S. Autophagy: A promising target for triple negative breast cancers. Pharmacol Res 2021; 175:106006. [PMID: 34843961 DOI: 10.1016/j.phrs.2021.106006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/16/2021] [Accepted: 11/23/2021] [Indexed: 01/18/2023]
Abstract
Triple negative breast cancer (TNBC) is the most aggressive type of breast cancers which constitutes about 15% of all breast cancer cases and characterized by negative expression of hormonal receptors and human epidermal growth factor receptor 2 (HER2). Thus, endocrine and HER2 targeted therapies are not effective toward TNBCs, and they mainly rely on chemotherapy and surgery for treatment. Despite recent advances in chemotherapy, 40% of TNBC patients develop a metastatic relapse and recurrence. Therefore, understanding the molecular profile of TNBC is warranted to identify targets that can be selected for the development of a new and effective therapeutic approach. Autophagy is an internal defensive mechanism that allows the cells to survive under different stressors. It has been well known that autophagy exerts a crucial role in cancer progression. The critical role of autophagy in TNBC progression is emerging in recent years. This review will discuss autophagic pathway, how autophagy affects TNBC progression and recent therapeutic approaches that can target autophagy as a new treatment modality.
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Affiliation(s)
- Yomna S Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Josef Gillson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia
| | - Patric J Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia; Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Kolling Institute of Medical Research, St Leonards, NSW, Australia.
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16
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Nasaruddin ML, Tajul Arifin K. Application of Metabolomics in the Study of Starvation-Induced Autophagy in Saccharomyces cerevisiae: A Scoping Review. J Fungi (Basel) 2021; 7:987. [PMID: 34829274 PMCID: PMC8619235 DOI: 10.3390/jof7110987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 11/18/2022] Open
Abstract
This scoping review is aimed at the application of the metabolomics platform to dissect key metabolites and their intermediates to observe the regulatory mechanisms of starvation-induced autophagy in Saccharomyces cerevisiae. Four research papers were shortlisted in this review following the inclusion and exclusion criteria. We observed a commonly shared pathway undertaken by S. cerevisiae under nutritional stress. Targeted and untargeted metabolomics was applied in either of these studies using varying platforms resulting in the annotation of several different observable metabolites. We saw a commonly shared pathway undertaken by S. cerevisiae under nutritional stress. Following nitrogen starvation, the concentration of cellular nucleosides was altered as a result of autophagic RNA degradation. Additionally, it is also found that autophagy replenishes amino acid pools to sustain macromolecule synthesis. Furthermore, in glucose starvation, nucleosides were broken down into carbonaceous metabolites that are being funneled into the non-oxidative pentose phosphate pathway. The ribose salvage allows for the survival of starved yeast. Moreover, acute glucose starvation showed autophagy to be involved in maintaining ATP/energy levels. We highlighted the practicality of metabolomics as a tool to better understand the underlying mechanisms involved to maintain homeostasis by recycling degradative products to ensure the survival of S. cerevisiae under starvation. The application of metabolomics has extended the scope of autophagy and provided newer intervention targets against cancer as well as neurodegenerative diseases in which autophagy is implicated.
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Affiliation(s)
| | - Khaizurin Tajul Arifin
- Department of Biochemistry, Faculty of Medicine, National University of Malaysia Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia;
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17
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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18
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Devenport SN, Singhal R, Radyk MD, Taranto JG, Kerk SA, Chen B, Goyert JW, Jain C, Das NK, Oravecz-Wilson K, Zhang L, Greenson JK, Chen YE, Soleimanpour SA, Reddy P, Lyssiotis CA, Shah YM. Colorectal cancer cells utilize autophagy to maintain mitochondrial metabolism for cell proliferation under nutrient stress. JCI Insight 2021; 6:e138835. [PMID: 34138755 PMCID: PMC8328084 DOI: 10.1172/jci.insight.138835] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Cancer cells reprogram cellular metabolism to maintain adequate nutrient pools to sustain proliferation. Moreover, autophagy is a regulated mechanism to break down dysfunctional cellular components and recycle cellular nutrients. However, the requirement for autophagy and the integration in cancer cell metabolism is not clear in colon cancer. Here, we show a cell-autonomous dependency of autophagy for cell growth in colorectal cancer. Loss of epithelial autophagy inhibits tumor growth in both sporadic and colitis-associated cancer models. Genetic and pharmacological inhibition of autophagy inhibits cell growth in colon cancer–derived cell lines and patient-derived enteroid models. Importantly, normal colon epithelium and patient-derived normal enteroid growth were not decreased following autophagy inhibition. To couple the role of autophagy to cellular metabolism, a cell culture screen in conjunction with metabolomic analysis was performed. We identified a critical role of autophagy to maintain mitochondrial metabolites for growth. Loss of mitochondrial recycling through inhibition of mitophagy hinders colon cancer cell growth. These findings have revealed a cell-autonomous role of autophagy that plays a critical role in regulating nutrient pools in vivo and in cell models, and it provides therapeutic targets for colon cancer.
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Affiliation(s)
- Samantha N Devenport
- Cellular and Molecular Biology.,Departments of Molecular & Integrative Physiology
| | | | | | | | | | - Brandon Chen
- Cellular and Molecular Biology.,Departments of Molecular & Integrative Physiology
| | | | - Chesta Jain
- Departments of Molecular & Integrative Physiology
| | - Nupur K Das
- Departments of Molecular & Integrative Physiology
| | | | - Li Zhang
- Departments of Molecular & Integrative Physiology
| | | | | | | | - Pavan Reddy
- Hematology & Oncology.,Rogel Cancer Center, and
| | - Costas A Lyssiotis
- Departments of Molecular & Integrative Physiology.,Rogel Cancer Center, and.,Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor Michigan, USA
| | - Yatrik M Shah
- Cellular and Molecular Biology.,Departments of Molecular & Integrative Physiology.,Rogel Cancer Center, and.,Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor Michigan, USA
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19
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Stepka P, Vsiansky V, Raudenska M, Gumulec J, Adam V, Masarik M. Metabolic and Amino Acid Alterations of the Tumor Microenvironment. Curr Med Chem 2021; 28:1270-1289. [PMID: 32031065 DOI: 10.2174/0929867327666200207114658] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/13/2020] [Accepted: 01/17/2020] [Indexed: 11/22/2022]
Abstract
Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and the effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely, alterations in the metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show the effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in a healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from the metabolism of other tissues. Findings from different tissues are, therefore, not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.
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Affiliation(s)
- Petr Stepka
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Vit Vsiansky
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-61600 Brno, Czech Republic
| | - Michal Masarik
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-61600 Brno, Czech Republic
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20
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Xu F, Wu Q, Li L, Gong J, Huo R, Cui W. Icariside II: Anticancer Potential and Molecular Targets in Solid Cancers. Front Pharmacol 2021; 12:663776. [PMID: 33981241 PMCID: PMC8107468 DOI: 10.3389/fphar.2021.663776] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 03/12/2021] [Indexed: 12/23/2022] Open
Abstract
Icariside II, an active flavonoid, is extracted from the traditional Chinese medicinal herb Epimedii. It possesses multiple biological and pharmacological properties, including anti-inflammatory, anticancer, and anti-osteoporotic properties. In recent years, apoptosis has become the hot spot in anticancer therapies. Icariside II exerts positive effects on inducing apoptosis and inhibiting proliferation in various cancers. The antitumorigenic activity of Icariside II was also proven through cell cycle arrest, triggering autophagy, reducing cellular metabolism, and inhibiting cancer metastasis and tumor-associated angiogenesis. Additionally, Icariside II, as a natural product, contributed to a synergistic effect alongside chemotherapeutic drugs. Due to its poor aqueous solubility and permeability, more strategies were developed to improve its therapeutic effects. This review aimed to summarize the chemopreventive properties of Icariside II in solid tumors and reveal its underlying molecular mechanisms.
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Affiliation(s)
- Fei Xu
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.,First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qiaolan Wu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Li
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Gong
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ran Huo
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenqiang Cui
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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21
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du Plessis M, Davis T, Loos B, Pretorius E, de Villiers WJS, Engelbrecht AM. Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A. Cytokine Growth Factor Rev 2021; 59:71-83. [PMID: 33727011 DOI: 10.1016/j.cytogfr.2021.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.
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Affiliation(s)
- M du Plessis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa.
| | - T Davis
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - B Loos
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - E Pretorius
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa
| | - W J S de Villiers
- African Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
| | - A M Engelbrecht
- Department of Physiological Sciences, University of Stellenbosch, Stellenbosch, South Africa; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg Campus, South Africa
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22
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Autophagy suppression plays a role in parenteral nutrition-associated lung injury. Clin Nutr 2021; 40:560-570. [DOI: 10.1016/j.clnu.2020.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/02/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023]
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23
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Harnessing the Co-vulnerabilities of Amino Acid-Restricted Cancers. Cell Metab 2021; 33:9-20. [PMID: 33406406 PMCID: PMC7837405 DOI: 10.1016/j.cmet.2020.12.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 12/18/2022]
Abstract
Sustained proliferative potential of cancer cells creates heightened energetic and biosynthetic demands. The resulting overt dependence of cancer cells on unperturbed nutrient supply has prompted a widespread interest in amino acid restriction strategies as potential cancer therapeutics. However, owing to rapid signaling and metabolic reprogramming in cancer cells, the prospects for success of amino acid restriction approaches remain unclear. We thus recognize that the identification of co-vulnerabilities of amino acid-restricted cancers may inform actionable targets for effective combined interventions. In this perspective, we outline the current state of key cellular mechanisms underlying adaptation to amino acid restriction and discuss the role of signal transduction pathways governing cancer cell resistance to amino acid restriction, with potential ramifications for the design of future therapeutic efforts.
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Cocco S, Leone A, Piezzo M, Caputo R, Di Lauro V, Di Rella F, Fusco G, Capozzi M, Gioia GD, Budillon A, De Laurentiis M. Targeting Autophagy in Breast Cancer. Int J Mol Sci 2020; 21:E7836. [PMID: 33105796 PMCID: PMC7660056 DOI: 10.3390/ijms21217836] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.
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Affiliation(s)
- Stefania Cocco
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (A.L.); (A.B.)
| | - Michela Piezzo
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Roberta Caputo
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Vincenzo Di Lauro
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Francesca Di Rella
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Giuseppina Fusco
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Monica Capozzi
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Germira di Gioia
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (A.L.); (A.B.)
| | - Michelino De Laurentiis
- Breast Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 53, 80131 Napoli, Italy; (M.P.); (R.C.); (V.D.L.); (F.D.R.); (G.F.); (M.C.); (G.d.G.)
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Naito K, Kanki K. Glycolytic inhibition by resveratrol prevents myoblast cell death caused by glucose deprivation and hypoxia; a possible application to the three-dimensional tissue construction. J Biosci Bioeng 2020; 131:90-97. [PMID: 32950383 DOI: 10.1016/j.jbiosc.2020.08.010] [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: 05/03/2020] [Revised: 07/30/2020] [Accepted: 08/22/2020] [Indexed: 11/28/2022]
Abstract
Decreased cell viability resulting from a severe condition of nutrients deprivation and hypoxia has been the major obstacle in three-dimensional (3D) tissue construction. Therefore, technical improvement which prevents cell death caused by starvation and low oxygen is desired for the development of large, thick tissues. We focused on the anti-glycolytic effect of resveratrol (RSV), a naturally-occurring polyphenol known as a caloric restriction mimetic, and investigated its cytoprotective effect in two-dimensional (2D) and 3D-cell culture using H9c2 rat myoblast cells. Glucose deprivation by culturing with low glucose media caused time- and dose-dependent cell death in H9c2 cells. In contrast, RSV treatment at 100 μM significantly increased the cell viability by preventing cell death. RSV showed anti-glycolytic effect associated with a down-regulation of glycolytic genes (GLUT1, PKM2) and glucose uptake activity, and increased the activation of AMP-activated protein kinase (AMPK), an essential cellular energy sensor activated in the condition of energy deprivation. RSV treatment markedly improved the viability of myoblast cells cultured in a hypoxic, low glucose condition and attenuated the up-regulation of glycolytic genes by hypoxic response. In 3D-cultured model, spheroids constructed with RSV-treated cells showed improved cell viability and intact histological appearance compared with control. These results suggest that glycolytic inhibition by RSV decreases the glucose usage of myoblast cells, therefore, prevents cell death caused by nutrient deprivation and hypoxic condition. Our finding provides useful information to improve cell viability in a condition that nutrients and oxygen are low in supply, and be a possible application to the 3D-tissue construction.
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Affiliation(s)
- Kyoko Naito
- Department of Biomedical Engineering, Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan.
| | - Keita Kanki
- Department of Biomedical Engineering, Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan.
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Satou M, Wang J, Nakano-Tateno T, Teramachi M, Suzuki T, Hayashi K, Lamothe S, Hao Y, Kurata H, Sugimoto H, Chik C, Tateno T. L-type amino acid transporter 1, LAT1, in growth hormone-producing pituitary tumor cells. Mol Cell Endocrinol 2020; 515:110868. [PMID: 32579901 DOI: 10.1016/j.mce.2020.110868] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 05/03/2020] [Accepted: 05/11/2020] [Indexed: 11/22/2022]
Abstract
Pituitary tumors (PTs) can cause significant mortality and morbidity due to limited therapeutic options. L-type amino acid transporters (LATs), in particular, the LAT1 isoform, is expressed in a variety of tumor cells. Pharmacological inhibition or genetic ablation of LAT1 can suppress leucine transport into cancer cells, resulting in suppression of cancer cell growth. However, roles of LAT1 in PTs have not been elucidated. Therefore, we assessed LAT1 expression in PTs and evaluated a LAT1-specific inhibitor, JPH203, on rat somatomammotroph tumor cells, GH4 cells. GH4 cells dominantly express LAT1 mRNA rather than other LAT isoforms, whereas LAT2 transcripts were most abundant in normal rat pituitary tissues. JPH203 inhibited leucine uptake and cell growth in GH4 cells in a concentration-dependent manner, and appeared to be independent of the mechanistic target, the rapamycin pathway. Although JPH203 did not induce apoptosis, it suppressed growth hormone production in GH4 cells. Also, genetic downregulation of LAT1 showed similar effects on cell growth and hormone production. These results indicated that restriction of LAT1 substrates by JPH203 modulated both cell growth and hormone production. In conclusion, LAT1 may be a new therapeutic target for PTs because its inhibition leads to suppression of cell growth as well as hormone production. JPH203 may represent a promising drug for clinical use in patients with PTs, with the potential of hormonal control and tumor suppression.
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Affiliation(s)
- Motoyasu Satou
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Jason Wang
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Tae Nakano-Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Mariko Teramachi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | | | - Keitaro Hayashi
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Shawn Lamothe
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Yubin Hao
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Harley Kurata
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada
| | - Hiroyuki Sugimoto
- Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
| | - Constance Chik
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Toru Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
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Yang J, Ueharu H, Mishina Y. Energy metabolism: A newly emerging target of BMP signaling in bone homeostasis. Bone 2020; 138:115467. [PMID: 32512164 PMCID: PMC7423769 DOI: 10.1016/j.bone.2020.115467] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022]
Abstract
Energy metabolism is the process of generating energy (i.e. ATP) from nutrients. This process is indispensable for cell homeostasis maintenance and responses to varying conditions. Cells require energy for growth and maintenance and have evolved to have multiple pathways to produce energy. Both genetic and functional studies have demonstrated that energy metabolism, such as glucose, fatty acid, and amino acid metabolism, plays important roles in the formation and function of bone cells including osteoblasts, osteocytes, and osteoclasts. Dysregulation of energy metabolism in bone cells consequently disturbs the balance between bone formation and bone resorption. Metabolic diseases have also been reported to affect bone homeostasis. Bone morphogenic protein (BMP) signaling plays critical roles in regulating the formation and function of bone cells, thus affecting bone development and homeostasis. Mutations of BMP signaling-related genes in mice have been reported to show abnormalities in energy metabolism in many tissues, including bone. In addition, BMP signaling correlates with critical signaling pathways such as mTOR, HIF, Wnt, and self-degradative process autophagy to coordinate energy metabolism and bone homeostasis. These findings will provide a newly emerging target of BMP signaling and potential therapeutic strategies and the improved management of bone diseases. This review summarizes the recent advances in our understanding of (1) energy metabolism in regulating the formation and function of bone cells, (2) function of BMP signaling in whole body energy metabolism, and (3) mechanistic interaction of BMP signaling with other signaling pathways and biological processes critical for energy metabolism and bone homeostasis.
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Affiliation(s)
- Jingwen Yang
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
| | - Hiroki Ueharu
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
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Functions and Implications of Autophagy in Colon Cancer. Cells 2019; 8:cells8111349. [PMID: 31671556 PMCID: PMC6912527 DOI: 10.3390/cells8111349] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/24/2019] [Accepted: 10/28/2019] [Indexed: 02/08/2023] Open
Abstract
Autophagy is an essential function to breakdown cellular proteins and organelles to recycle for new nutrient building blocks. In colorectal cancer, the importance of autophagy is becoming widely recognized as it demonstrates both pro- and anti-tumorigenic functions. In colon cancer, cell autonomous and non-autonomous roles for autophagy are essential in growth and progression. However, the mechanisms downstream of autophagy (to reduce or enhance tumor growth) are not well known. Additionally, the signals that activate and coordinate autophagy for tumor cell growth and survival are not clear. Here, we highlight the context- and cargo-dependent role of autophagy in proliferation, cell death, and cargo breakdown.
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Du N, Li XH, Bao WG, Wang B, Xu G, Wang F. Resveratrol‑loaded nanoparticles inhibit enterovirus 71 replication through the oxidative stress‑mediated ERS/autophagy pathway. Int J Mol Med 2019; 44:737-749. [PMID: 31173159 DOI: 10.3892/ijmm.2019.4211] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 05/23/2019] [Indexed: 11/05/2022] Open
Abstract
A number of studies have demonstrated that resveratrol (RES) has a variety of biological functions, including cardiovascular protective effects, treatment of mutations, and anti‑inflammatory, anti‑tumor and antiviral effects. In the present study, RES‑loaded nanoparticles (RES‑NPs) were used to protect rhabdosarcoma (RD) cells from enterovirus 71 (EV71) infection, and the relevant mechanisms were also explored. An amphiphilic copolymer, monomethoxy poly (ethylene glycol)‑b‑poly (D,L‑lactide), was used as vehicle material, and RES‑NPs with necessitated drug‑loading content and suitable sizes were prepared under optimized conditions. RES‑NPs exhibited the ability to inhibit the increase of intracellular oxidative stress. The prospective mechanism for the function of RES‑NPs suggested was that RES‑NPs may inhibit the oxidative stress‑mediated PERK/eIF2α/ATF4 signaling pathway, downregulate the autophagy pathway and resist EV71‑induced RD cells injury. Furthermore, RES‑NPs treatment markedly inhibited the secretion of inflammatory factors, including interleukin (IL)‑6, IL‑8 and tumor necrosis factor‑α elicited by EV71 infection. Concomitantly, inhibitors of oxidative stress, endoplasmic reticulum stress (ERS) or autophagy were demonstrated to negate the anti‑inflammatory and antiviral effects of RES‑NPs on EV71‑infected RD cells. These results demonstrated that RES‑NPs attenuated EV71‑induced viral replication and inflammatory effects by inhibiting the oxidative stress‑mediated ERS/autophagy signaling pathway. In view of their safety and efficiency, these RES‑NPs have potential applications in protecting RD cells from EV71 injury.
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Affiliation(s)
- Na Du
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiao-Hua Li
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wan-Guo Bao
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Bin Wang
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guang Xu
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Feng Wang
- Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Séité S, Pioche T, Ory N, Plagnes-Juan E, Panserat S, Seiliez I. The Autophagic Flux Inhibitor Bafilomycine A1 Affects the Expression of Intermediary Metabolism-Related Genes in Trout Hepatocytes. Front Physiol 2019; 10:263. [PMID: 30936838 PMCID: PMC6431650 DOI: 10.3389/fphys.2019.00263] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/28/2019] [Indexed: 12/28/2022] Open
Abstract
Autophagy is an evolutionarily conserved process of cellular self-eating which emerged these last years as a major adaptive metabolic response to various stresses such as fasting, hypoxia, or environmental pollutants. However, surprisingly very few data is currently available on its role in fish species which are directly exposed to frequent environmental perturbations. Here, we report that the treatment of fasted trout hepatocytes with the autophagy inhibitor Bafilomycine A1 lowered the mRNA levels of many of the gluconeogenesis-related genes and increased those of genes involved in intracellular lipid stores. Concurrently, intracellular free amino acid levels dropped and the expression of the main genes involved in the endoplasmic reticulum (ER) stress exhibited a sharp increase in autophagy inhibited cells. Together these results highlight the strong complexity of the crosstalk between ER, autophagy and metabolism and support the importance of considering this function in future studies on metabolic adaptation of fish to environmental stresses.
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Affiliation(s)
- Sarah Séité
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
- Evonik Rexim, Ham, France
- Evonik Nutrition and Care GmbH, Hanau, Germany
| | - Tracy Pioche
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
| | - Nicolas Ory
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
| | - Elisabeth Plagnes-Juan
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
| | - Stéphane Panserat
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
| | - Iban Seiliez
- INRA, E2S UPPA, UMR 1419, Nutrition, Métabolisme, Aquaculture, University of Pau and Pays de l’Adour, Saint-Pée-sur-Nivelle, France
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Das CK, Parekh A, Parida PK, Bhutia SK, Mandal M. Lactate dehydrogenase A regulates autophagy and tamoxifen resistance in breast cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1004-1018. [PMID: 30878502 DOI: 10.1016/j.bbamcr.2019.03.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/25/2019] [Accepted: 03/10/2019] [Indexed: 01/14/2023]
Abstract
Estrogen receptor (ER) antagonist, tamoxifen has been universally used for the treatment of the ER-positive breast cancer; however, the inevitable emergence of resistance to tamoxifen obstructs the successful treatment of this cancer. So, there is an immediate requirement for the search of a novel therapeutic target for treatment of this cancer. Acquired tamoxifen-resistant breast cancer cell lines MCF-7 (MCF-7/TAM-R) and T47D (T47D/TAM-R) showed higher apoptotic resistance accompanied by induction of pro-survival autophagy compared to their parental cells. Besides, tamoxifen resistance was associated with reduced production of ATP and with overexpression of glycolytic pathways, leading to induced autophagy to meet the energy demand. Further, our study revealed that LDHA; one of the key molecules of glycolysis in association with Beclin-1 induced pro-survival autophagy in tamoxifen-resistant breast cancer. Mechanistically, pharmacological and genetic inhibition of LDHA reduced the pro-survival autophagy, with the restoration of apoptosis and reverting back the EMT like phenomena noticed in tamoxifen-resistant breast cancer. In total, targeting LDHA opened a novel strategy to interrupt autophagy and tamoxifen resistance in breast cancer.
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Affiliation(s)
- Chandan Kanta Das
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Aditya Parekh
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Pratap Kumar Parida
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Sujit Kumar Bhutia
- Department of Life Science, National Institute of Technology, Rourkela, India
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India.
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Li C, Chen K, Jia M, Ding X, Jiang Z, Li L, Zhang D. AMPK promotes survival and adipogenesis of ischemia-challenged ADSCs in an autophagy-dependent manner. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1498-1510. [PMID: 30296594 DOI: 10.1016/j.bbalip.2018.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 09/28/2018] [Accepted: 10/05/2018] [Indexed: 12/24/2022]
Abstract
Some studies have shown that transplanted fat tissues usually cannot survive for long if adipose-derived stem cells (ADSCs) are removed from the tissues in advance. It is more meaningful to explore the mechanism mediating survival and differentiation of ADSCs in the transplanted microenvironment. AMP-activated protein kinase (AMPK) has been shown to be one of the energy receptors that regulate many aspects of cellular metabolism. AMPK activation has been implicated in models of adult ischemic injury, but the mechanism and the regulating effects of AMPK on survival and adipogenesis of transplanted ADSCs are still little known. In this study, we simulated the transplanted microenvironment using oxygen-glucose deprivation (OGD) to test the survival and adipogenesis of ADSCs. We found that OGD treatment triggered significant apoptosis and promoted autophagy. Simultaneously, OGD hindered the differentiation of ADSCs into mature adipocytes. After inhibiting AMPK, the OGD-induced apoptosis rate increased but autophagy was inhibited. The adipogenesis level also decreased. To show that the effects of AMPK on apoptosis and adipogenesis were autophagy-dependent, we pre-inhibited or pre-promoted autophagy with siATG7 or rapamycin while blocking AMPK. We found that inhibiting or improving autophagy exacerbated or alleviated the role of AMPK prohibition in apoptosis and adipogenesis. Furthermore, we showed that AMPK inhibition significantly lowered ULK1 activity but promoted mTOR activity, so that to inhibit autophagy. Our study shows that AMPK plays a protective role in maintaining survival and adipogenesis of OGD-challenged ADSCs partly by positively regulating autophagy. AMPK positively regulates autophagy by inhibiting mTOR but promoting ULK1 activity in OGD condition.
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Affiliation(s)
- Chichi Li
- Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China
| | - Kewei Chen
- Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China
| | - Minghui Jia
- Otolaryngology Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China
| | - Xi Ding
- Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China
| | - Zipei Jiang
- Department of Ophthalmology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China
| | - Liqun Li
- Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China.
| | - Dan Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, PR China.
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The role of autophagy in morphogenesis and stem cell maintenance. Histochem Cell Biol 2018; 150:721-732. [PMID: 30382373 DOI: 10.1007/s00418-018-1751-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2018] [Indexed: 12/21/2022]
Abstract
During embryonic development, cells need to undergo a number of morphological changes that are decisive for the shaping of the embryo's body, initiating organogenesis and differentiation into functional tissues. These remodeling processes are accompanied by profound changes in the cell membrane, the cytoskeleton, organelles, and extracellular matrix composition. While considerably detailed insight into the role of autophagy in stem cells biology has been gained in the recent years, information regarding the participation of autophagy in morphogenetic processes is only sparse. This review, therefore, focuses on the role of autophagy in cell morphogenesis through its regulatory activity in TGFβ signaling, expression of adhesion molecules and cell cycle modification. It also discusses the role of autophagy in stem cell maintenance which is very fundamental for cell renewal and replacement during development, pathogenesis of certain diseases and development of therapies. We are thus addressing here perspectives for further potentially rewarding research topics.
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Routes to cell death in animal and plant kingdoms: from classic apoptosis to alternative ways to die—a review. RENDICONTI LINCEI-SCIENZE FISICHE E NATURALI 2018. [DOI: 10.1007/s12210-018-0704-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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