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Ruan Z, Wang Y, Shi L, Yang XJ. Progress of research on glucose transporter proteins in hepatocellular carcinoma. World J Hepatol 2025; 17:104715. [DOI: 10.4254/wjh.v17.i3.104715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/02/2025] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs’ roles in HCC and to determine the most effective ways to translate these findings into clinical practice.
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Affiliation(s)
- Zheng Ruan
- The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yan Wang
- Division of Personnel, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
| | - Lei Shi
- Department of General Surgery, The Second people’s Hospital of Lanzhou, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jun Yang
- Department of General Surgery, Gansu Provincial People’s Hospital, Lanzhou 730000, Gansu Province, China
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Flausino LE, Carrasco AGM, Furuya TK, Tuan WJ, Chammas R. Impact of SGLT2 inhibitors on survival in gastrointestinal cancer patients undergoing chemotherapy and/or radiotherapy: a real-world data retrospective cohort study. BMC Cancer 2025; 25:542. [PMID: 40133838 PMCID: PMC11938601 DOI: 10.1186/s12885-025-13966-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 03/19/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND The role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) drugs in the management of diabetes and cardiovascular disease is well-established, but emerging evidence suggests potential effects on cancer outcomes, including gastrointestinal (GI) cancers. We conducted an extensive, sex-oriented, real-world data analysis to investigate whether SGLT2i can enhance GI cancer outcomes when used alongside standard therapies such as chemotherapy and radiotherapy. METHODS The study applied a retrospective cohort design with data from the TriNetX research database ( https://trinetx.com ), examining GI cancer patients treated with chemotherapy and/or radiotherapy between 2013 and 2023. The intervention cohort consisted of Gl cancer patients who received SGLT2i, while the control cohort did not. A 5-year follow-up period was used, and baseline characteristics were balanced using a 1:1 propensity score matching technique. Cox proportional-hazards and logistic regression models assessed mortality and morbidity risks between the cohorts. RESULTS The study included 6,389 male and 3,457 female patients with GI cancer (ICD-10: C15-C25). The use of SGLT2i was significantly associated with improved survival for both male (HR 0.568; 95% CI 0.534-0.605) and female (HR 0.561; 95% CI 0.513-0.614) patients undergoing chemotherapy and/or radiotherapy. SGLT2i use also correlated significantly with lower hospitalisation rates both in male (OR 0.684; 95% CI 0.637-0.734) and female (OR, 0.590; 95% CI 0.536-0.650) patients. The analysis of GI cancer subtypes also demonstrated similar benefits, without significant adverse effects. CONCLUSIONS Repurposing SGLT2 inhibitors for cancer treatment could potentially improve outcomes for GI cancer patients without causing significant side effects. Further clinical trials are needed to confirm these findings and establish the optimal condition for its application in GI cancer treatment.
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Affiliation(s)
- Lucas E Flausino
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Alexis Germán Murillo Carrasco
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Tatiane Katsue Furuya
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil
| | - Wen-Jan Tuan
- Department of Family and Community Medicine, and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Roger Chammas
- Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- Comprehensive Center for Precision Oncology, Universidade de São Paulo, São Paulo, Brazil.
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Yin J, Li J, Wang H. Disulfidptosis: a novel gene-based signature predicts prognosis and immunotherapy efficacy of pancreatic adenocarcinoma. Discov Oncol 2025; 16:308. [PMID: 40072658 PMCID: PMC11904034 DOI: 10.1007/s12672-025-02053-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Disulfidptosis, a novel form of disulfide stress-induced cell death involved in tumor progression, hasn't be well defined the function in tumor progression. And the clinical impacts of disulfidptosis-related genes (DRGs) in pancreatic adenocarcinoma (PAAD) remain largely unclear. In this study, we identified two distinct disulfidptosis subtypes and found that multilayer DRG alterations were associated with prognosis and TME infiltration characteristics. A three-gene prognostic signature was constructed to predict prognosis, and its clinical significance was characterized in the TCGA-PAAD cohort. The disulfidptosis signature was significantly correlated with prognosis, molecular subtype, CD8 T-cell infiltration, response to immune checkpoint inhibitors and chemotherapeutic drug sensitivity, and its predictive capability in PAAD patients was validated in multiple cohorts. Meanwhile, two anti-PD-L1 immunotherapy cohorts confirmed that low-risk patients exhibited substantially enhanced clinical response and treatment advantages. Furthermore, the expression patterns of DRGs were validated by quantitative real-time PCR. The expression and prognostic predictive capability of GLUT1 were verified by 87 PAAD patients from our cohort. These findings may help us understand the roles of DRGs in PAAD and the molecular characterization of disulfidptosis subtypes. The disulfidptosis signature could be a promising biomarker for prognosis, molecular subtypes, TME infiltration characteristics and immunotherapy efficacy.
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Affiliation(s)
- Jingyang Yin
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing, China
- University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China
| | - Jian Li
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710000, China
| | - Huaizhi Wang
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing University, Chongqing, China.
- Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing, China.
- University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China.
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Zeng X, Na R, Yang L, Zhao X, Huang X. Inhibition mechanism understanding from molecular dynamics simulation of the interactions between several flavonoids and proton-dependent glucose transporter. J Biomol Struct Dyn 2025; 43:1278-1289. [PMID: 38084742 DOI: 10.1080/07391102.2023.2291544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/11/2023] [Indexed: 01/16/2025]
Abstract
Proton-dependent glucose transporters as important drug targets can have different protonation states and adjust their conformational state under different pHs. So based on this character, research on its inhibition mechanism is a significant work. In this article, to study its inhibitory mechanism, we performed the molecular dynamics of several classical flavonoid molecules (Three inhibitors Phloretin, Naringenin, Resveratrol. Two non-inhibitors Isoliquiritigenin, Butein) with glucose transporters under two distinct environmental pHs. The results show inhibitors occupy glucose binding sites (GLN137, ILE255, ASN256) and have strong hydrophobic interactions with proteins through core moiety (C6-Cn-C6). In addition, inhibitors had better inhibitory effects in protonation state. In contrast, non-inhibitors can not occupy glucose binding sites (GLN137, ILE255, ASN256), thus they do not have intense interactions with the protein. It is suggested that favorable inhibitors should effectively take up the glucose-binding site (GLN137, ILE255, ASN256) and limit the protein conformational changes.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Xianyang Zeng
- School of Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, China
| | - Risong Na
- Collaborative Innovation Center of Henan Grain Crops, National Key Laboratory of Wheat and Maize Crop Science, College of Plant Protection, Henan Agricultural University, Zhengzhou, China
| | - Lianjuan Yang
- Department of Medical Mycology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xi Zhao
- School of Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, China
| | - Xuri Huang
- School of Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, China
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Liu Y, Han J, Shioya A, Zhang YX, Dung VA, Oyama T, Guo X, Yang Q, Ito T, Yamada S. The immunohistochemical combination of low SGLT2 expression and high PRDX4 expression independently predicts shortened survival in patients undergoing surgical resection for hepatoblastoma. Diagn Pathol 2025; 20:2. [PMID: 39773476 PMCID: PMC11708186 DOI: 10.1186/s13000-025-01596-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Hepatoblastoma (HB) is the most common malignant solid tumor of the liver in children and is a fatal disease with a poor prognosis. Therefore, indicators that can be used for the early prediction of the HB prognosis are necessary. Sodium glucose cotransporter 2 (SGLT2) is a glucose transporter protein present in the proximal renal tubules. Studies have shown that SGLT2 is associated with the occurrence of tumors and is upregulated in various tumors. Peroxiredoxin 4 (PRDX4) is an antioxidant enzyme with a secretory function and is located in the cytoplasmic endoplasmic reticulum. Recent reports have suggested that it is closely related to the development and prognosis of various cancers. To some degree, this is highly suggestive of the interplay between SGLT2 and PRDX4. METHODS In the present study, clinical data and post-surgical paraffin-embedded specimens from 75 HB patients were collected, and hematoxylin and eosin and immunohistochemical staining of SGLT2 and PRDX4 were used to analyze their expression and correlation with the clinicopathological features and prognosis. RESULTS We found that low SGLT2 and high PRDX4 expression predicted a significantly shorter survival and worse clinical condition in HB patients. Furthermore, when low SGLT2 expression was combined with high PRDX4 expression, the event-free survival and overall survival were significantly reduced. Univariate and multivariate Cox proportional hazards analyses showed that low SGLT2 and high PRDX4 expression in HB were independent prognostic factors for the survival after surgical resection. CONCLUSION The immunohistochemical combination of low SGLT2 and high PRDX4 expression can independently predict a poor prognosis in HB patients.
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Affiliation(s)
- Yao Liu
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan.
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China.
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan.
| | - Jia Han
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
| | - Akihiro Shioya
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
| | - Yang-Xian Zhang
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
- Department of Geriatrics, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Vu Anh Dung
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
- Department of Joint Surgery, 103 Military Hospital, Vietnam Military Medical University, Hanoi, 151000, Vietnam
| | - Takeru Oyama
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
| | - Xin Guo
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
- Research Center, First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050011, China
| | - Qian Yang
- Department of Spleen and Stomach Diseases, First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050011, China
- Hebei Key Laboratory of Turbidity Toxin Syndrome, First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050011, China
| | - Tohru Ito
- Department of Gastroenterological Endoscopy, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Director of Kanazawa Medical University Himi Municipal Hospital, Toyama, 935-8531, Japan
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, Ishikawa, 920-0293, Japan
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa, 920-0293, Japan
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Wu R, Zhu H, He Q, Yuan T, Yang B. Metabolic reprogramming in KRAS-mutant cancers: Proven targetable vulnerabilities and potential therapeutic strategies. Drug Discov Today 2024; 29:104220. [PMID: 39481592 DOI: 10.1016/j.drudis.2024.104220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 10/16/2024] [Accepted: 10/24/2024] [Indexed: 11/02/2024]
Abstract
Kras (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), one of the most frequently mutated oncogenes in the human genome, is considered 'untargetable'. Although specific KRASG12C inhibitors have been developed, their overall impact is limited, highlighting the need for further research on targeting KRAS-mutant cancers. Metabolic abnormalities are key hallmarks of cancer, with KRAS-driven tumors exhibiting traits like glycolysis upregulation, glutamine addiction, lipid droplet accumulation, highly active macropinocytosis, and metabolic reprogramming-associated tumor microenvironment remodeling. Targeting these unique metabolic characteristics offers a promising strategy for new cancer treatments. This review summarizes recent advances in our understanding of the metabolic network in KRAS-mutated tumor cells, discusses potential targetable vulnerabilities, and outlines clinical developments in relevant therapies, while also addressing challenges to improve strategies against these aggressive cancers.
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Affiliation(s)
- Ruilin Wu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, China.
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Youssef A, Sahgal A, Das S. Radioresistance and brain metastases: a review of the literature and applied perspective. Front Oncol 2024; 14:1477448. [PMID: 39540151 PMCID: PMC11557554 DOI: 10.3389/fonc.2024.1477448] [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: 08/08/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Intracranial metastatic disease is a serious complication of cancer, treated through surgery, radiation, and targeted therapies. The central role of radiation therapy makes understanding the radioresistance of metastases a priori a key interest for prognostication and therapeutic development. Although historically defined clinic-radiographically according to tumour response, developments in new techniques for delivering radiation treatment and understanding of radioprotective mechanisms led to a need to revisit the definition of radioresistance in the modern era. Factors influencing radioresistance include tumour-related factors (hypoxia, cancer stem cells, tumour kinetics, tumour microenvironment, metabolic alterations, tumour heterogeneity DNA damage repair, non-coding RNA, exosomes, methylomes, and autophagy), host-related factors (volume effect & dose-limiting non-cancerous tissue, pathophysiology, and exosomes), technical factors, and probabilistic factors (cell cycle and random gravity of DNA damage). Influences on radioresistance are introduced and discussed in the context of brain metastases.
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Affiliation(s)
- Andrew Youssef
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Arjun Sahgal
- Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Hospital, Toronto, ON, Canada
| | - Sunit Das
- Division of Neurosurgery, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
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Zhang X, Tian H, Chen Y, Liang B, Nice EC, Huang C, Xie N, Zheng S. A metal-organic nanoframework for efficient colorectal cancer immunotherapy by the cGAS-STING pathway activation and immune checkpoint blockade. J Nanobiotechnology 2024; 22:592. [PMID: 39343911 PMCID: PMC11441132 DOI: 10.1186/s12951-024-02836-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 09/04/2024] [Indexed: 10/01/2024] Open
Abstract
Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5'-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.
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Affiliation(s)
- Xiaodian Zhang
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, the First Clinical College & the First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China
| | - Hailong Tian
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yang Chen
- School of Basic Medical Sciences, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Baichuan Liang
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Na Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
| | - Shaojiang Zheng
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The Hainan Branch of National Clinical Research Center for Cancer, the First Clinical College & the First Affiliated Hospital, Hainan Medical University, Haikou, 570102, China.
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, 571199, China.
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Yang Y, Pu J, Yang Y. Glycolysis and chemoresistance in acute myeloid leukemia. Heliyon 2024; 10:e35721. [PMID: 39170140 PMCID: PMC11336864 DOI: 10.1016/j.heliyon.2024.e35721] [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: 10/17/2023] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
While traditional high-dose chemotherapy can effectively prolong the overall survival of acute myeloid leukemia (AML) patients and contribute to better prognostic outcomes, the advent of chemoresistance is a persistent challenge to effective AML management in the clinic. The therapeutic resistance is thought to emerge owing to the heterogeneous and adaptable nature of tumor cells when exposed to exogenous stimuli. Recent studies have focused on exploring metabolic changes that may afford novel opportunities to treat AML, with a particular focus on glycolytic metabolism. The Warburg effect, a hallmark of cancer, refers to metabolism of glucose through glycolysis under normoxic conditions, which contributes to the development of chemoresistance. Despite the key significance of this metabolic process in the context of malignant transformation, the underlying molecular mechanisms linking glycolysis to chemoresistance in AML remain incompletely understood. This review offers an overview of the current status of research focused on the relationship between glycolytic metabolism and AML resistance to chemotherapy, with a particular focus on the contributions of glucose transporters, key glycolytic enzymes, signaling pathways, non-coding RNAs, and the tumor microenvironment to this relationship. Together, this article will provide a foundation for the selection of novel therapeutic targets and the formulation of new approaches to treating AML.
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Affiliation(s)
- Yan Yang
- Department of Neonatology, Zigong Maternity and Child Health Care Hospital, Zigong, Sichuan, 643000, China
| | - Jianlin Pu
- Department of Psychiatry, The Zigong Affiliated Hospital of Southwest Medical University, Zigong mental health Center, Zigong Institute of Brain Science, Zigong, Sichuan, 643000, China
| | - You Yang
- Department of Pediatrics (Children Hematological Oncology), Birth Defects and Childhood Hematological Oncology Laboratory, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou, Sichuan, 646000, China
- The Second Hospital, Centre for Reproductive Medicine, Advanced Medical Research Institute, Key Laboratory for Experimental Teratology of the Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China
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Zhang J, Huang X, Zhang T, Gu C, Zuo W, Fu L, Dong Y, Liu H. Antitumorigenic potential of Lactobacillus-derived extracellular vesicles: p53 succinylation and glycolytic reprogramming in intestinal epithelial cells via SIRT5 modulation. Cell Biol Toxicol 2024; 40:66. [PMID: 39110260 PMCID: PMC11306434 DOI: 10.1007/s10565-024-09897-y] [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: 12/22/2023] [Accepted: 06/21/2024] [Indexed: 08/10/2024]
Abstract
OBJECTIVE Colorectal cancer progression involves complex cellular mechanisms. This study examines the effects of Lactobacillus plantarum-derived extracellular vesicles (LEVs) on the SIRT5/p53 axis, focusing on glycolytic metabolic reprogramming and abnormal proliferation in intestinal epithelial cells. METHODS LEVs were isolated from Lactobacillus plantarum and incubated with Caco-2 cells. Differential gene expression was analyzed through RNA sequencing and compared with TCGA-COAD data. Key target genes and pathways were identified using PPI network and pathway enrichment analysis. Various assays, including RT-qPCR, EdU staining, colony formation, flow cytometry, and Western blotting, were used to assess gene expression, cell proliferation, and metabolic changes. Co-immunoprecipitation confirmed the interaction between SIRT5 and p53, and animal models were employed to validate in vivo effects. RESULTS Bioinformatics analysis indicated the SIRT5/p53 axis as a critical pathway in LEVs' modulation of colorectal cancer. LEVs were found to inhibit colorectal cancer cell proliferation and glycolytic metabolism by downregulating SIRT5, influencing p53 desuccinylation. In vivo, LEVs regulated this axis, reducing tumor formation in mice. Clinical sample analysis showed that SIRT5 and p53 succinylation levels correlated with patient prognosis. CONCLUSION Lactobacillus-derived extracellular vesicles play a pivotal role in suppressing colonic tumor formation by modulating the SIRT5/p53 axis. This results in decreased glycolytic metabolic reprogramming and reduced proliferation in intestinal epithelial cells.
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Affiliation(s)
- Jingbo Zhang
- Department of Spleen and Stomach Disease, Yubei District Hospital of Traditional Chinese Medicine, Chongqing, 401120, China
| | - Xiumei Huang
- Department of Digestion, Rongchang District People's Hospital of Chongqing, No.3, North Guangchang Road, Changyuan Street, Rongchang District, Chongqing, 402460, China
| | - Tingting Zhang
- Department of Digestion, Rongchang District People's Hospital of Chongqing, No.3, North Guangchang Road, Changyuan Street, Rongchang District, Chongqing, 402460, China
| | - Chongqi Gu
- Department of Pediatrics, Rongchang District People's Hospital, Chongqing, 402460, China
| | - Wei Zuo
- Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 400016, China
- Department of Pharmacology, Academician Workstation, Changsha Medical University, Changsha, 410219, China
| | - Lijuan Fu
- Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, 400016, China
- Department of Pharmacology, Academician Workstation, Changsha Medical University, Changsha, 410219, China
| | - Yiping Dong
- Department of Digital Medicine, Department of Bioengineering and Imaging, Army Medical University, Chongqing, 400038, China
| | - Hao Liu
- Department of Pediatrics, Rongchang District People's Hospital, Chongqing, 402460, China.
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Ni X, Lu CP, Xu GQ, Ma JJ. Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy. Acta Pharmacol Sin 2024; 45:1533-1555. [PMID: 38622288 PMCID: PMC11272797 DOI: 10.1038/s41401-024-01264-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 03/08/2024] [Indexed: 04/17/2024]
Abstract
Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.
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Affiliation(s)
- Xuan Ni
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China
| | - Cheng-Piao Lu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Guo-Qiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China.
- Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
| | - Jing-Jing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China.
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12
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Miller ZA, Muthuswami S, Mueller A, Ma RZ, Sywanycz SM, Naik A, Huang L, Brody RM, Diab A, Carey RM, Lee RJ. GLUT1 inhibitor BAY-876 induces apoptosis and enhances anti-cancer effects of bitter receptor agonists in head and neck squamous carcinoma cells. Cell Death Discov 2024; 10:339. [PMID: 39060287 PMCID: PMC11282258 DOI: 10.1038/s41420-024-02106-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca2+ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 (SLC2A1) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.
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Affiliation(s)
- Zoey A Miller
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Pharmacology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Sahil Muthuswami
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Arielle Mueller
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ray Z Ma
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Sarah M Sywanycz
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Anusha Naik
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Lily Huang
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Robert M Brody
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ahmed Diab
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Ryan M Carey
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
| | - Robert J Lee
- Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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13
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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14
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Lv S, Zhang Z, Li Z, Ke Q, Ma X, Li N, Zhao X, Zou Q, Sun L, Song T. TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells. J Biol Chem 2024; 300:107270. [PMID: 38599381 PMCID: PMC11098960 DOI: 10.1016/j.jbc.2024.107270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/14/2024] [Accepted: 03/25/2024] [Indexed: 04/12/2024] Open
Abstract
Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet, cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall shed insight into cancer progression and benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. It remains unclear whether and how TFE3 responds to glucose starvation. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.
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Affiliation(s)
- Suli Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zongbiao Zhang
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenyong Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Ke
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianyun Ma
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Neng Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingli Zou
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lidong Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Tanjing Song
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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15
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Ben Ali F, Qmichou Z, Oukabli M, Dakka N, Bakri Y, Eddouks M, Ameziane El Hassani R. Alteration of glucose metabolism and expression of glucose transporters in ovarian cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:384-399. [PMID: 38745772 PMCID: PMC11090687 DOI: 10.37349/etat.2024.00224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/09/2024] [Indexed: 05/16/2024] Open
Abstract
Aerobic glycolysis also known as the Warburg effect, remains a hallmark of various cancers, including ovarian cancer. Cancer cells undergo metabolic changes to sustain their tumorigenic properties and adapt to environmental conditions, such as hypoxia and nutrient starvation. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, develop resistance to chemotherapy, maintain cancer stem cell phenotype, and escape anti-tumor immune responses. Glucose transporters (GLUTs), which play a pivotal role as the rate-limiting step in glycolysis, are frequently overexpressed in a variety of tumors, including ovarian cancer. Multiple oncoproteins can regulate GLUT proteins, promoting tumor proliferation, migration, and metastasis, either dependent or independent of glycolysis. This review examines the alteration of GLUT proteins, particularly GLUT1, in ovarian cancer and its impact on cancer initiation, progression, and resistance to treatment. Additionally, it highlights the role of these proteins as biomarkers for diagnosis and prognosis in ovarian cancer, and delves into novel therapeutic strategies currently under development that target GLUT isoforms.
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Affiliation(s)
- Fatima Ben Ali
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Zineb Qmichou
- Medical Biotechnology Center, Moroccan Foundation for Advanced Science, Innovation and Research (MAScIR), Rabat 10001, Morocco
| | - Mohamed Oukabli
- Department of Anatomical Pathology, Military Hospital of Instruction Mohammed V (HMIMV-R), Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Nadia Dakka
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Youssef Bakri
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
| | - Mohammed Eddouks
- Team of Ethnopharmacology and Pharmacognosy, Faculty of Sciences and Techniques Errachidia, Moulay Ismail University of Meknes, Errachidia BP 509, Morocco
| | - Rabii Ameziane El Hassani
- Laboratory of Biology of Human Pathologies (BioPatH), Faculty of Sciences, Mohammed V University in Rabat, Rabat 10001, Morocco
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16
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Tang H, Guo Y, Gan S, Chen Z, Dong M, Lin L, Chen H, Ji X, Xian M, Shi X, Tao A, Lv Y, Yao L, Chen R, Li S, Li J. GLUT1 mediates the release of HMGB1 from airway epithelial cells in mixed granulocytic asthma. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167040. [PMID: 38281711 DOI: 10.1016/j.bbadis.2024.167040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 01/18/2024] [Accepted: 01/22/2024] [Indexed: 01/30/2024]
Abstract
Asthma is quite heterogenous and can be categorized as eosinophilic, mixed granulocytic (presence of both eosinophils and neutrophils in the airways) and neutrophilic. Clinically, mixed granulocytic asthma (MGA) often tends to be severe and requires large doses of corticosteroids. High mobility group box 1 (HMGB1) is one of the epithelium-derived alarmins that contributes to type 2 inflammation and asthma. This study was aimed to investigate the role of glucose transporter 1 (GLUT1) in modulation of airway epithelial HMGB1 production in MGA. Induced sputum and bronchial biopsy specimens were obtained from healthy subjects and asthma patients. BALB/c mice, the airway epithelial cell line BEAS-2B, or primary human bronchial epithelial cells (HBECs) were immunized with allergens. Intracellular and extracellular HMGB1 were both detected. The role of GLUT1 was assessed by using a pharmacological antagonist BAY876. MGA patients have a significant higher sputum HMGB1 level than the health and subjects with other inflammatory phenotypes. Nuclear-to-cytoplasmic translocation of HMGB1 was also observed in the bronchial epithelia. Allergen exposure markedly induced GLUT1 expression in murine lungs and cultured epithelial cells. Pharmacological antagonism of GLUT1 with BAY876 dramatically decreased airway hyperresponsiveness, neutrophil and eosinophil accumulation, as well as type 2 inflammation in murine models of MGA. Besides, the allergen-induced up-regulation of HMGB1 was also partly recovered by BAY876, accompanied by inhibited secretion into the airway lumen. In vitro, treatment with BAY876 relieved the allergen-induced over-expression and secretion of HMGB1 in airway epithelia. Taken together, our data indicated that GLUT1 mediates bronchial epithelial HMGB1 release in MGA.
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Affiliation(s)
- Haixiong Tang
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yubiao Guo
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Sudan Gan
- Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zemin Chen
- Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Meihua Dong
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Liqin Lin
- Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Huifang Chen
- The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
| | - Xiaolong Ji
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mo Xian
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xu Shi
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ailin Tao
- The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
| | - Yanhua Lv
- Department of Respiratory and Critical Care Medicine, Zhongshan City People's Hospital, Zhongshan, Gongdong, China
| | - Lihong Yao
- Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ruchong Chen
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Shiyue Li
- Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Jing Li
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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17
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Zhang Z, Liang X, Yang X, Liu Y, Zhou X, Li C. Advances in Nanodelivery Systems Based on Metabolism Reprogramming Strategies for Enhanced Tumor Therapy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:6689-6708. [PMID: 38302434 DOI: 10.1021/acsami.3c15686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Tumor development and metastasis are closely related to the complexity of the metabolism network. Recently, metabolism reprogramming strategies have attracted much attention in tumor metabolism therapy. Although there is preliminary success of metabolism therapy agents, their therapeutic effects have been restricted by the effective reaching of the tumor sites of drugs. Nanodelivery systems with unique physical properties and elaborate designs can specifically deliver to the tumors. In this review, we first summarize the research progress of nanodelivery systems based on tumor metabolism reprogramming strategies to enhance therapies by depleting glucose, inhibiting glycolysis, depleting lactic acid, inhibiting lipid metabolism, depleting glutamine and glutathione, and disrupting metal metabolisms combined with other therapies, including chemotherapy, radiotherapy, photodynamic therapy, etc. We further discuss in detail the advantages of nanodelivery systems based on tumor metabolism reprogramming strategies for tumor therapy. As well as the opportunities and challenges for integrating nanodelivery systems into tumor metabolism therapy, we analyze the outlook for these emerging areas. This review is expected to improve our understanding of modulating tumor metabolisms for enhanced therapy.
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Affiliation(s)
- Zongquan Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiaoya Liang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xi Yang
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yan Liu
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Xiangyu Zhou
- Department of Thyroid and Vascular Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
- Basic Medicine Research Innovation Center for Cardiometabolic Disease, Ministry of Education, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Chunhong Li
- Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China
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Zhang J, Xu X, Zhao Y, Ren C, Gu M, Zhang H, Wu P, Wang Y, Kong L, Han C. Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa. JOURNAL OF NATURAL PRODUCTS 2024; 87:2-13. [PMID: 38117981 DOI: 10.1021/acs.jnatprod.3c00613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Abstract
The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.
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Affiliation(s)
- Jinghan Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Xiao Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Yu Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Chunling Ren
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Mengzhen Gu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Haili Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Peiye Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Yun Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Lingyi Kong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
| | - Chao Han
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P.R. China
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Chang M, Ellmaker K, Esposito A, Lauricella A, Pa S, Roberts M, Kurt RA. The Impact of Tumor-Associated Macrophages Found at Mammary Carcinoma Sites is Dependent Upon the Tumor Type. Immunol Invest 2023; 52:909-924. [PMID: 37647339 DOI: 10.1080/08820139.2023.2252463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
BACKGROUND Previously, we reported that tumor-associated macrophages (TAM) at early sites of mammary carcinoma showed a decrease in ATP production rate and a higher dependence on oxidative phosphorylation. METHODS Since these changes can result from activation of AMP-activated protein kinase (AMPK) and glucose transporter 1 (Glut1) during metabolic stress, we investigated whether the TAM showed increased expression of ampk and glut1, as well as another indicator of metabolic stress, pkm2. Indeed, the TAM exhibited significant expression of pkm2, glut1, and ampk. RESULTS Bone marrow-derived macrophages (BMDM) co-cultured with 4T1, EMT6, and 168 in vitro similarly showed increased expression of pkm2, glut1, and ampk. Moreover, lactate, which is expressed at significant levels by all three tumors, induced expression of these same genes in BMDM suggesting that lactate may induce a metabolic stress response in these TAM. Yet, the three different mammary carcinoma models benefited from different targeting strategies. Macrophage depletion studies revealed that the TAM contributed to growth of the EMT6 tumor and metastasis of the 4T1 tumor. Targeting the stress response with the Integrated Stress Response Inhibitor (ISRIB), which targets eIF2, impacted 168 tumor progression, and ISRIB as well as FX-11, which targets lactate dehydrogenase, impacted 4T1 tumor progression and metastasis. CONCLUSIONS Collectively, these data demonstrate that targeting TAM or metabolism at early tumor sites can impact tumor progression. However, variability in the responses underscore the fact that the impact of macrophages differs even within three different syngeneic mammary carcinoma models.
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Affiliation(s)
- Musea Chang
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | | | - Abigail Esposito
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | | | - Sophea Pa
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | - Meghan Roberts
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
| | - Robert A Kurt
- Department of Biology, Lafayette College, Easton, Pennsylvania, USA
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20
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Wu X, Ma Y, Wang L, Qin X. A Route for Investigating Psoriasis: From the Perspective of the Pathological Mechanisms and Therapeutic Strategies of Cancer. Int J Mol Sci 2023; 24:14390. [PMID: 37762693 PMCID: PMC10532365 DOI: 10.3390/ijms241814390] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/20/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
Psoriasis is an incurable skin disease that develops in about two-thirds of patients before the age of 40 and requires lifelong treatment; its pathological mechanisms have not been fully elucidated. The core pathological process of psoriasis is epidermal thickening caused by the excessive proliferation of epidermal keratinocytes, which is similar to the key feature of cancer; the malignant proliferation of cancer cells causes tumor enlargement, suggesting that there is a certain degree of commonality between psoriasis and cancer. This article reviews the pathological mechanisms that are common to psoriasis and cancer, including the interaction between cell proliferation and an abnormal immune microenvironment, metabolic reprogramming, and epigenetic reprogramming. In addition, there are common therapeutic agents and drug targets between psoriasis and cancer. Thus, psoriasis and cancer share a common pathological mechanisms-drug targets-therapeutic agents framework. On this basis, it is proposed that investigating psoriasis from a cancer perspective is beneficial to enriching the research strategies related to psoriasis.
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Affiliation(s)
- Xingkang Wu
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, China; (Y.M.); (L.W.)
| | | | | | - Xuemei Qin
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, China; (Y.M.); (L.W.)
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21
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Li Y, Tang S, Shi X, Lv J, Wu X, Zhang Y, Wang H, He J, Zhu Y, Ju Y, Zhang Y, Guo S, Yang W, Yin H, Chen L, Gao D, Jin G. Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer. Cell Rep Med 2023; 4:101162. [PMID: 37597521 PMCID: PMC10518604 DOI: 10.1016/j.xcrm.2023.101162] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 06/14/2023] [Accepted: 07/26/2023] [Indexed: 08/21/2023]
Abstract
Metabolic reprogramming is known as an emerging mechanism of chemotherapy resistance, but the metabolic signatures of pancreatic ductal adenocarcinomas (PDACs) remain unclear. Here, we characterize the metabolomic profile of PDAC organoids and classify them into glucomet-PDAC (high glucose metabolism levels) and lipomet-PDAC (high lipid metabolism levels). Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression. Pharmacological inhibition of GLUT1 or G6PD enhances the chemotherapy response of glucomet-PDAC. Our findings uncover potential metabolic heterogeneity related to differences in chemotherapy sensitivity in PDAC and develop a promising pharmacological strategy for patients with chemotherapy-resistant glucomet-PDAC through the combination of chemotherapy and GLUT1/ALDOB/G6PD axis inhibitors.
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Affiliation(s)
- Yunguang Li
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shijie Tang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaohan Shi
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China
| | - Jingwen Lv
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Innovation Center for Intervention of Chronic Disease and Promotion of Health, Chinese Academy of Sciences (CAS), Shanghai 200031, China
| | - Xueyuan Wu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yehan Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huan Wang
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China
| | - Juan He
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiqin Zhu
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yi Ju
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yajuan Zhang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shiwei Guo
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China
| | - Weiwei Yang
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China.
| | - Huiyong Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Innovation Center for Intervention of Chronic Disease and Promotion of Health, Chinese Academy of Sciences (CAS), Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
| | - Dong Gao
- State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Gang Jin
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
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22
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Li M, Sun S, Bian Z, Yao S, Liu M, You X, Li M. SNHG15 promotes chemoresistance and glycolysis in colorectal cancer. Pathol Res Pract 2023; 246:154480. [PMID: 37148838 DOI: 10.1016/j.prp.2023.154480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Revised: 03/27/2023] [Accepted: 04/22/2023] [Indexed: 05/08/2023]
Abstract
Long noncoding RNAs (lncRNAs) play an important role in tumor progression. Small nucleolar RNA host gene 15 (SNHG15) is a lncRNA that has been confirmed to play an oncogenic role in multiple cancer types. However, its role in glycolysis and chemoresistance in colorectal cancer (CRC) is unclear. The expression of SNHG15 in CRC was analyzed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases by bioinformatics methods. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate cell viability. Cell sensitivity to 5-fluorouracil (5-FU) was detected by CCK-8. Glucose absorption and lactate production were used to evaluate the impact of SNHG15 on glycolysis. RNA-seq, real-time fluorescence quantitative reverse transcription PCR (RT-qPCR) and Western blotting (WB) were used to reveal the potential molecular mechanism of SNHG15 in CRC. SNHG15 was upregulated in CRC tissues compared with paired noncancerous tissues. Ectopic SNHG15 expression increased proliferation, 5-FU chemoresistance, and glycolysis in CRC cells. In contrast, SNHG15 knockdown inhibited CRC proliferation, 5-FU chemoresistance and glycolysis. Multiple pathways, including apoptosis and glycolysis, were potentially regulated by SNHG15 based on RNA-seq and pathway enrichment analyses. RT-qPCR and WB experiments confirmed that SNHG15 promoted the expression of TYMS, BCL2, GLUT1 and PKM2 in CRC cells. In conclusion, SNHG15 promotes 5-FU chemoresistance and glycolysis in CRC by potentially regulating the expression of TYMS, BCL2, GLUT1 and PKM2 and appears to be a new target for cancer therapy.
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Affiliation(s)
- Min Li
- Pharmacy Department, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214100, China.
| | - Shengbai Sun
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
| | - Zehua Bian
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
| | - Surui Yao
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China
| | - Meng Liu
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Xiaohong You
- Pharmacy Department, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214100, China.
| | - Min Li
- Pharmacy Department, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214100, China
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23
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Chelakkot C, Chelakkot VS, Shin Y, Song K. Modulating Glycolysis to Improve Cancer Therapy. Int J Mol Sci 2023; 24:2606. [PMID: 36768924 PMCID: PMC9916680 DOI: 10.3390/ijms24032606] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
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Affiliation(s)
| | - Vipin Shankar Chelakkot
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Youngkee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung Song
- College of Pharmacy, Duksung Women’s University, Seoul 01366, Republic of Korea
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24
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Disorders of cancer metabolism: The therapeutic potential of cannabinoids. Biomed Pharmacother 2023; 157:113993. [PMID: 36379120 DOI: 10.1016/j.biopha.2022.113993] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022] Open
Abstract
Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy. Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms. This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.
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25
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Kulin A, Kucsma N, Bohár B, Literáti-Nagy B, Korányi L, Cserepes J, Somogyi A, Sarkadi B, Szabó E, Várady G. Genetic Modulation of the GLUT1 Transporter Expression-Potential Relevance in Complex Diseases. BIOLOGY 2022; 11:1669. [PMID: 36421383 PMCID: PMC9687623 DOI: 10.3390/biology11111669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 12/01/2023]
Abstract
The human GLUT1 (SLC2A1) membrane protein is the key glucose transporter in numerous cell types, including red cells, kidney, and blood-brain barrier cells. The expression level of this protein has a role in several diseases, including cancer and Alzheimer's disease. In this work, to investigate a potential genetic modulation of the GLUT1 expression level, the protein level was measured in red cell membranes by flow cytometry, and the genetic background was analyzed by qPCR and luciferase assays. We found significant associations between red cell GLUT1 levels and four single nucleotide polymorphisms (SNP) in the coding SLC2A1 gene, that in individuals with the minor alleles of rs841848, rs1385129, and rs11537641 had increased, while those having the variant rs841847 had decreased erythrocyte GLUT1 levels. In the luciferase reporter studies performed in HEK-293T and HepG2 cells, a similar SNP-dependent modulation was observed, and lower glucose, serum, and hypoxic condition had variable, cell- and SNP-specific effects on luciferase expression. These results should contribute to a more detailed understanding of the genetic background of membrane GLUT1 expression and its potential role in associated diseases.
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Affiliation(s)
- Anna Kulin
- Doctoral School of Molecular Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - Nóra Kucsma
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - Balázs Bohár
- Doctoral School of Biology, Eötvös Loránd University, 1117 Budapest, Hungary
| | | | | | | | - Anikó Somogyi
- 2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary
| | - Balázs Sarkadi
- Doctoral School of Molecular Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - Edit Szabó
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
| | - György Várady
- Doctoral School of Molecular Medicine, Semmelweis University, 1085 Budapest, Hungary
- Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary
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26
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Choi SYC, Ribeiro CF, Wang Y, Loda M, Plymate SR, Uo T. Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer. Biomolecules 2022; 12:1590. [PMID: 36358940 PMCID: PMC9687810 DOI: 10.3390/biom12111590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 08/27/2023] Open
Abstract
There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.
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Affiliation(s)
- Stephen Y. C. Choi
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Caroline Fidalgo Ribeiro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY 10021, USA
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
- Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY 10021, USA
- New York Genome Center, New York, NY 10013, USA
| | - Stephen R. Plymate
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, 850 Republican St., Seattle, WA 98109, USA
- Geriatrics Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Takuma Uo
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, 850 Republican St., Seattle, WA 98109, USA
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27
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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28
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Temre MK, Yadav S, Goel Y, Pandey SK, Kumar A, Singh SM. Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity. Front Oncol 2022; 12:925666. [PMID: 35847943 PMCID: PMC9279700 DOI: 10.3389/fonc.2022.925666] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/01/2022] [Indexed: 12/21/2022] Open
Abstract
Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential. However, several aspects of the underlying mechanisms remain obscure. To understand this better, tumor cells of thymic origin designated as Dalton's lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Adding fructose to the culture medium containing glutor reversed the latter's inhibitory action on tumor cell survival. These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Thus, the novel findings of this study will have a long-lasting clinical significance in evaluating and optimizing the use of glutor in anticancer therapeutic strategies.
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Affiliation(s)
- Mithlesh Kumar Temre
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Saveg Yadav
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Yugal Goel
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Shrish Kumar Pandey
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Ajay Kumar
- Deparment of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi, India
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29
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Dong P, Wang F, Taheri M, Xiong Y, Ihira K, Kobayashi N, Konno Y, Yue J, Watari H. Long Non-Coding RNA TMPO-AS1 Promotes GLUT1-Mediated Glycolysis and Paclitaxel Resistance in Endometrial Cancer Cells by Interacting With miR-140 and miR-143. Front Oncol 2022; 12:912935. [PMID: 35712514 PMCID: PMC9195630 DOI: 10.3389/fonc.2022.912935] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/29/2022] [Indexed: 01/05/2023] Open
Abstract
Increased glycolysis in tumor cells is frequently associated with drug resistance. Overexpression of glucose transporter-1 (GLUT1) promotes the Warburg effect and mediates chemoresistance in various cancers. Aberrant GLUT1 expression is considered as an essential early step in the development of endometrial cancer (EC). However, its role in EC glycolysis and chemoresistance and the upstream mechanisms underlying GLUT1 overexpression, remain undefined. Here, we demonstrated that GLUT1 was highly expressed in EC tissues and cell lines and that high GLUT1 expression was associated with poor prognosis in EC patients. Both gain-of-function and loss-of-function studies showed that GLUT1 increased EC cell proliferation, invasion, and glycolysis, while also making them resistant to paclitaxel. The long non-coding RNA TMPO-AS1 was found to be overexpressed in EC tissues and to be negatively associated with EC patient outcomes. RNA-immunoprecipitation and luciferase reporter assays confirmed that TMPO-AS1 elevated GLUT1 expression by directly binding to two critical tumor suppressor microRNAs (miR-140 and miR-143). Downregulation of TMPO-AS1 remarkably reduced EC cell proliferation, invasion, glycolysis, and paclitaxel resistance in EC cells. This study established that dysregulation of the TMPO-AS1-miR-140/miR-143 axis contributes to glycolysis and drug resistance in EC cells by up-regulating GLUT1 expression. Thus, inhibiting TMPO-AS1 and GLUT1 may prove beneficial in overcoming glycolysis-induced paclitaxel resistance in patients with EC.
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Affiliation(s)
- Peixin Dong
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Feng Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Mohammad Taheri
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Ying Xiong
- Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kei Ihira
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Noriko Kobayashi
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yosuke Konno
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.,Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Hidemichi Watari
- Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo, Japan
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30
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Xu X, Wang C, Zhang P, Gao X, Guan W, Wang F, Li X, Yuan J, Dou H, Xu G. Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death. Int J Biol Sci 2022; 18:374-385. [PMID: 34975339 PMCID: PMC8692137 DOI: 10.7150/ijbs.66602] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/08/2021] [Indexed: 11/23/2022] Open
Abstract
Anti-cancer chemo-drugs can cause a rapid elevation of intracellular reactive oxygen species (ROS) levels. An imbalance in ROS production and elimination systems leads to cancer cell resistance to chemotherapy. This study aimed to evaluate the mechanism and effect of ROS on multidrug resistance in various human chemoresistant cancer cells by detecting the changes in the amount of ROS, the expression of ROS-related and glycolysis-related genes, and cell death. We found that ROS was decreased while oxidative phosphorylation was increased in chemoresistant cells. We verified that the chemoresistance of cancer cells was achieved in two ways. First, chemoresistant cells preferred oxidative phosphorylation instead of anaerobic glycolysis for energy generation, which increased ATPase activity and produced much more ATP to provide energy. Second, ROS-scavenging systems were enhanced in chemoresistant cancer cells, which in turn decreased ROS amount and thus inhibited chemo-induced cell death. Our in vitro and in vivo photodynamic therapy further demonstrated that elevated ROS production efficiently inhibited chemo-drug resistance and promoted chemoresistant cell death. Taken together, targeting ROS systems has a great potential to treat cancer patients with chemoresistance.
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Affiliation(s)
- Xiaolin Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Chenglong Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Peipei Zhang
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Xuzhu Gao
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China
| | - Fanchen Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xin Li
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jia Yuan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Hongjing Dou
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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31
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Petruzzelli M, Ferrer M, Schuijs MJ, Kleeman SO, Mourikis N, Hall Z, Perera D, Raghunathan S, Vacca M, Gaude E, Lukey MJ, Jodrell DI, Frezza C, Wagner EF, Venkitaraman AR, Halim TYF, Janowitz T. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia. Cancers (Basel) 2022; 14:963. [PMID: 35205709 PMCID: PMC8870098 DOI: 10.3390/cancers14040963] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
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Affiliation(s)
- Michele Petruzzelli
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Miriam Ferrer
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Martijn J. Schuijs
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Sam O. Kleeman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Nicholas Mourikis
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Zoe Hall
- Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK;
| | - David Perera
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Shwethaa Raghunathan
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Michele Vacca
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK;
| | - Edoardo Gaude
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Michael J. Lukey
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
| | - Duncan I. Jodrell
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Christian Frezza
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
| | - Erwin F. Wagner
- Laboratory Genes and Disease, Department of Laboratory Medicine Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria;
- Laboratory Genes and Disease, Department of Dermatology, Medical University of Vienna (MUV), 1090 Vienna, Austria
| | - Ashok R. Venkitaraman
- Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK; (M.P.); (M.F.); (D.P.); (E.G.); (C.F.)
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Timotheus Y. F. Halim
- CRUK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge CB2 0RE, UK; (M.J.S.); (S.R.); (D.I.J.); (T.Y.F.H.)
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; (S.O.K.); (N.M.); (M.J.L.)
- Northwell Health Cancer Institute, New Hyde Park, NY 11042, USA
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32
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Amahong K, Yan M, Li J, Yang N, Liu H, Bi X, Vuitton DA, Lin R, Lü G. EgGLUT1 Is Crucial for the Viability of Echinococcus granulosus sensu stricto Metacestode: A New Therapeutic Target? Front Cell Infect Microbiol 2021; 11:747739. [PMID: 34858873 PMCID: PMC8632494 DOI: 10.3389/fcimb.2021.747739] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 10/14/2021] [Indexed: 12/14/2022] Open
Abstract
Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by infection with the larvae of Echinococcus granulosus sensu lato (s.l.) cluster. It is urgent to identify novel drug targets and develop new drug candidates against CE. Glucose transporter 1 (GLUT1) is mainly responsible for the transmembrane transport of glucose to maintain its constant cellular availability and is a recent research hotspot as a drug target in various diseases. However, the role of GLUT1 in E. granulosus s.l. (EgGLUT1) was unknown. In this study, we cloned a conserved GLUT1 homology gene (named EgGLUT1-ss) from E. granulosus sensu stricto (s.s.) and found EgGLUT1-ss was crucial for glucose uptake and viability by the protoscoleces of E. granulosus s.s. WZB117, a GLUT1 inhibitor, inhibited glucose uptake by E. granulosus s.s. and the viability of the metacestode in vitro. In addition, WZB117 showed significant therapeutic activity in E. granulosus s.s.-infected mice: a 10 mg/kg dose of WZB117 significantly reduced the number and weight of parasite cysts (P < 0.05) as efficiently as the reference drug, albendazole. Our results demonstrate that EgGLUT1-ss is crucial for glucose uptake by the protoscoleces of E. granulosus s.s., and its inhibitor WZB117 has a therapeutic effect on CE.
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Affiliation(s)
- Kuerbannisha Amahong
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Mingzhi Yan
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Jintian Li
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Ning Yang
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hui Liu
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaojuan Bi
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Dominique A Vuitton
- French National Reference Centre for Echinococcosis, University Bourgogne Franche-Comté, Besançon, France
| | - Renyong Lin
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,Basic Medical College, Xinjiang Medical University, Urumqi, China
| | - Guodong Lü
- State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China.,WHO Collaborating Centre for Prevention and Care Management of Echinococcosis, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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33
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Li Q, Wen Y, Wang L, Chen B, Chen J, Wang H, Chen L. Hyperglycemia-induced accumulation of advanced glycosylation end products in fibroblast-like synoviocytes promotes knee osteoarthritis. Exp Mol Med 2021; 53:1735-1747. [PMID: 34759325 PMCID: PMC8639977 DOI: 10.1038/s12276-021-00697-6] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/04/2021] [Accepted: 09/12/2021] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is significantly associated with diabetes, but how hyperglycemia induces or aggravates OA has not been shown. The synovium plays a critical role in cartilage metabolism and substance exchange. Herein, we intended to investigate whether and how hyperglycemia affects the occurrence and progression of OA by influencing the synovium. In patients with knee OA and diabetes (DM OA), we found a more severe inflammatory response, higher endoplasmic reticulum stress (ERS) levels, and more advanced glycosylation end products (AGEs) accumulation in the synovium than in patients without diabetes. Subsequently, we found similar results in the DM OA group in a rat model. In the in vitro cocultivation system, high glucose-stimulated AGEs accumulation, ERS, and inflammation in rat fibroblast-like synoviocytes (FLSs), which resulted in chondrocyte degeneration due to inflammatory factors from FLSs. Furthermore, in the synovium of the DM OA group and FLSs treated with high glucose, the expression of glucose transporter 1 (GLUT1) and its regulatory factor hypoxia-inducible factor (HIF)-1α was increased significantly. Inhibitors of HIF-1α, GLUT1 or AGEs receptors attenuated the effect of high glucose on chondrocyte degradation in the FLS-chondrocyte coculture system. In summary, we demonstrated that hyperglycemia caused AGEs accumulation in FLSs via the HIF-1α-GLUT1 pathway, which increases the release of inflammatory factors from FLSs, subsequently inducing chondrocyte degradation and promoting OA progression.
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Affiliation(s)
- Qingxian Li
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yinxian Wen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.,Joint Disease Research Center of Wuhan University, Wuhan, 430071, China
| | - Linlong Wang
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Biao Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Jun Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Hui Wang
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. .,Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
| | - Liaobin Chen
- Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. .,Joint Disease Research Center of Wuhan University, Wuhan, 430071, China.
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Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4. Pharmaceuticals (Basel) 2021; 14:ph14101032. [PMID: 34681256 PMCID: PMC8537711 DOI: 10.3390/ph14101032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/26/2022] Open
Abstract
Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group.
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35
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He YF, Mai CT, Pan HD, Liu L, Zhou H, Xie Y. Targeting immunometabolism by active ingredients derived from traditional Chinese medicines for treatment of rheumatoid arthritis. CHINESE HERBAL MEDICINES 2021; 13:451-460. [PMID: 36119361 PMCID: PMC9476673 DOI: 10.1016/j.chmed.2021.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/06/2021] [Accepted: 09/15/2021] [Indexed: 01/19/2023] Open
Abstract
Rheumatoid arthritis (RA), the most common inflammatory arthropathy word wild, is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate. Metabolic mis-regulation has emerged as a fundamental pathogenesis of RA linked to immune cell dysfunction, while targeting immunometabolism provides a new and effective approach to regulate the immune responses and thus alleviate the symptom of RA. Recently, natural active compounds from traditional Chinese medicines (TCMs) have potential therapeutic effects on RA and regulating immunometabolism. In this review, in addition to updating the connection between cellular metabolism and cell function in immune cells of RA, we summarized that the anti-inflammatory mechanisms of the potential natural compounds from TCM by targeting metabolic reprogramming of immune cells, and discusses them as a rich resource for providing the new potential paradigm for the treatment of RA.
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Affiliation(s)
| | | | - Hu-dan Pan
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR), China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR), China
| | - Hua Zhou
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR), China
| | - Ying Xie
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau (SAR), China
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36
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MaruYama T, Kobayashi S, Shibata H, Chen W, Owada Y. Curcumin analog GO-Y030 boosts the efficacy of anti-PD-1 cancer immunotherapy. Cancer Sci 2021; 112:4844-4852. [PMID: 34529884 PMCID: PMC8645716 DOI: 10.1111/cas.15136] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 11/30/2022] Open
Abstract
Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD‐1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti‐PD‐1 antibody, is known to promote the proliferation of the Treg population in tumor‐infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO‐Y030, an antitumor chemical. GO‐Y030 inhibited the immune‐suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO‐Y030 inhibited the mTOR‐S6 axis in Tregs, which plays a pivotal role in their immune‐suppressive ability. GO‐Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF‐β + IL‐6; however, it did not prevent Th17 differentiation. Notably, GO‐Y030 significantly inhibited IL‐10 production from Th17 cells. In the tumor microenvironment, L‐lactate produced by tumors is known to support the suppressive ability of Tregs, and GO‐Y030 treatment inhibited L‐lactate production via metabolic changes. In addition, experiments in the B16‐F10 melanoma mouse model revealed that GO‐Y030 helped inhibit the anti‐PD‐1 immune checkpoint and reduce the Treg population in tumor‐infiltrating lymphocytes. Thus, GO‐Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti‐immune checkpoint inhibitors.
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Affiliation(s)
- Takashi MaruYama
- Mucosal Immunology Section, NIDCR, National Institute of Health, Bethesda, MD, USA.,Department of Immunology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Shuhei Kobayashi
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hiroyuki Shibata
- Department of Clinical Oncology, Graduate School of Medicine, Akita University, Akita, Japan
| | - WanJun Chen
- Mucosal Immunology Section, NIDCR, National Institute of Health, Bethesda, MD, USA
| | - Yuji Owada
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Miyagi, Japan
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37
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Liu H, Zhang Q, Song Y, Hao Y, Cui Y, Zhang X, Zhang X, Qin Y, Zhu G, Wang F, Dang J, Ma S, Zhang Y, Guo W, Li S, Guan F, Fan T. Long non-coding RNA SLC2A1-AS1 induced by GLI3 promotes aerobic glycolysis and progression in esophageal squamous cell carcinoma by sponging miR-378a-3p to enhance Glut1 expression. J Exp Clin Cancer Res 2021; 40:287. [PMID: 34517880 PMCID: PMC8436487 DOI: 10.1186/s13046-021-02081-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/20/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Emerging evidence demonstrates that lncRNAs play pivotal roles in tumor energy metabolism; however, the detailed mechanisms of lncRNAs in the regulation of tumor glycolysis remain largely unknown. METHODS The expression of SLC2A1-AS1 was investigated by TCGA, GEO dataset and qRT-PCR. The binding of GLI3 to SLC2A1-AS1 promoter was detected by Luciferase Reporter Assay System and Ago2-RIP assay. FISH was performed to determine the localization of SLC2A1-AS1 in ESCC cells. Double Luciferase Report assay was used to investigate the interaction of miR-378a-3p with SLC2A1-AS1 and Glut1. Gain-of-function and Loss-of-function assay were performed to dissect the function of SLC2A1-AS1/miR-378a-3p/Glut1 axis in ESCC progression in vitro and in vivo. RESULTS We identified a novel lncRNA SLC2A1-AS1 in ESCC. SLC2A1-AS1 was frequently overexpressed in ESCC tissues and cells, and its overexpression was associated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Importantly, GLI3 and SLC2A1-AS1 formed a regulatory feedback loop in ESCC cells. SLC2A1-AS1 promoted cell growth in vitro and in vivo, migration and invasion, and suppressed apoptosis, leading to EMT progression and increased glycolysis in ESCC cells. SLC2A1-AS1 functioned as ceRNA for sponging miR-378a-3p, resulting in Glut1 overexpression in ESCC cells. MiR-378a-3p inhibited cell proliferation and invasion as well as induced apoptosis, resulting in reduced glycolysis, which was partly reversed by SLC2A1-AS1 or Glut1 overexpression in ESCC cells. CONCLUSION SLC2A1-AS1 plays important roles in ESCC development and progression by regulating glycolysis, and SLC2A1-AS1/miR-378a-3p/Glut1 regulatory axis may be a novel therapeutic target in terms of metabolic remodeling of ESCC patients.
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Affiliation(s)
- Hongtao Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
| | - Qing Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.,Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yinsen Song
- Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yibin Hao
- Translational Medicine Research Center, Zhengzhou People's Hospital, Zhengzhou, 450003, Henan, China
| | - Yunxia Cui
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xin Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xueying Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Yue Qin
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Guangzhao Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Feng Wang
- Institute of Genomic Medicine, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China.,International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of pharmacy, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Jinghan Dang
- Department of Clinical Medicine, Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shanshan Ma
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Yanting Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Wenna Guo
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Shenglei Li
- Department of Pathology, the First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou, 450052, Henan, China.
| | - Fangxia Guan
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
| | - Tianli Fan
- Department of Pharmacology, School of Basic Medicine, Zhengzhou University, 100 Kexue Road, Zhengzhou, 450001, Henan, China.
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Miao J, Zhang L, Gao P, Zhao H, Xie X, Wang J. Chitosan-Based Glycolipid Conjugated siRNA Delivery System for Improving Radiosensitivity of Laryngocarcinoma. Polymers (Basel) 2021; 13:2929. [PMID: 34502969 PMCID: PMC8434167 DOI: 10.3390/polym13172929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 11/16/2022] Open
Abstract
Glucose Transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors, which is an important factor in radioresistance of laryngocarcinoma. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngocarcinoma. GLUT-1 siRNA was designed to inhibit the GLUT-1 expression, but the high molecular weight and difficult drug delivery limited the application. Herein, we constructed a glycolipid polymer chitosan oligosaccharide grafted stearic acid (CSSA) to conjugate siRNA via electrostatic interaction. The characteristics of CSSA and CSSA/siRNA were studied, as well as the radiosensitization effect of siRNA on human laryngocarcinoma epithelial (Hep-2) cells. Compared with the traditional commercial vector LipofectamineTM2000 (Lipo), CSSA exhibited lower cytotoxicity, more efficiently cellular uptake. Incubating with CSSA/siRNA, the survival rates of Hep-2 cells were significantly decreased comparing with either the group before transfection or Lipo/siRNA. CSSA is a promising carrier for efficient siRNA delivery and radiosensitization of laryngocarcinoma.
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Affiliation(s)
- Jing Miao
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (L.Z.); (P.G.); (H.Z.)
| | - Liwen Zhang
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (L.Z.); (P.G.); (H.Z.)
| | - Peng Gao
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (L.Z.); (P.G.); (H.Z.)
| | - Huawei Zhao
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (L.Z.); (P.G.); (H.Z.)
| | - Xianji Xie
- Department of Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Junyan Wang
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (L.Z.); (P.G.); (H.Z.)
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DeLiberty JM, Robb R, Gates CE, Bryant KL. Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain. Adv Cancer Res 2021; 153:267-304. [PMID: 35101233 DOI: 10.1016/bs.acr.2021.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.
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Affiliation(s)
- Jonathan M DeLiberty
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ryan Robb
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Claire E Gates
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kirsten L Bryant
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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40
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Li L, Liu P, Xie Y, Liu Y, Chen Z, Geng Y, Zhang L. Xanthatin inhibits human colon cancer cells progression via mTOR signaling mediated energy metabolism alteration. Drug Dev Res 2021; 83:119-130. [PMID: 34180556 DOI: 10.1002/ddr.21850] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/08/2021] [Accepted: 06/17/2021] [Indexed: 11/05/2022]
Abstract
Tumor cells exhibit higher glycolysis and rely on abnormal energy metabolism to produce ATP, which is essential for cell proliferation and migration. Abnormal energy metabolism inhibition is considered a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. This study evaluated the effect of xanthatin on the energy metabolism of human colon cancer cells. The results showed that xanthatin significantly inhibited the migration and invasion of human HT-29 and HCT-116 colon cancer cells. We found that xanthatin effectively reduced the production of ATP and promoted the accumulation of lactate. Xanthatin inhibited glycolysis which may be related to the reduction of glucose transporter 1 (Glut1) and monocarboxylate transporter 4 (MCT4) mRNA and protein levels. Concomitantly, xanthatin promoted complex II activity and oxidative phosphorylation (OXPHOS), resulting in mitochondrial damage and cell death in HT-29 cells. Furthermore, xanthatin inhibited the phosphorylation of mTOR, the phosphorylation of 4E-binding protein 1 (4E-BP1) and c-myc in HT-29 cells. Moreover, rapamycin, a mTOR inhibitor, could enhance the cytotoxicity effect in xanthatin treated HT-29 cells. Additionally, HT-29 cells transfected with si-mTOR aggravated xanthatin induced cell viability inhibition. Based on these results, we observed that the effect of xanthatin on energy metabolism may be related to its inhibition of the mTOR signaling pathway. Collectively, this study provides important insights into xanthatin's anticancer effect, which occurs by regulation of the energy metabolism of human colon cancer cells, and suggest that xanthatin has potential as a botanical drug against abnormal tumor energy metabolism.
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Affiliation(s)
- Lingli Li
- Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China
| | - Ping Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Yanbo Xie
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yunxiao Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Zhaolin Chen
- Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China.,Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yadi Geng
- Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China.,Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Lei Zhang
- Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China.,Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.,Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
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Pharmacological inhibition of GLUT1 as a new immunotherapeutic approach after myocardial infarction. Biochem Pharmacol 2021; 190:114597. [PMID: 33965393 DOI: 10.1016/j.bcp.2021.114597] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/01/2021] [Accepted: 05/04/2021] [Indexed: 11/21/2022]
Abstract
Myocardial infarction (MI) is one of the major contributors to cardiovascular morbidity and mortality. Excess inflammation significantly contributes to cardiac remodeling and heart failure after MI. Accumulating evidence has shown the central role of cellular metabolism in regulating the differentiation and function of cells. Metabolic rewiring is particularly relevant for proinflammatory responses induced by ischemia. Hypoxia reduces mitochondrial oxidative phosphorylation (OXPHOS) and induces increased reliance on glycolysis. Moreover, activation of a proinflammatory transcriptional program is associated with preferential glucose metabolism in leukocytes. An improved understanding of the mechanisms that regulate metabolic adaptations holds the potential to identify new metabolic targets and strategies to reduce ischemic cardiac damage, attenuate excess local inflammation and ultimately prevent the development of heart failure. Among possible drug targets, glucose transporter 1 (GLUT1) gained considerable interest considering its pivotal role in regulating glucose availability in activated leukocytes and the availability of small molecules that selectively inhibit it. Therefore, we summarize current evidence on the role of GLUT1 in leukocytes (focusing on macrophages and T cells) and non-leukocytes, including cardiomyocytes, endothelial cells and fibroblasts regarding ischemic heart disease. Beyond myocardial infarction, we can foresee the role of GLUT1 blockers as a possible pharmacological approach to limit pathogenic inflammation in other conditions driven by excess sterile inflammation.
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Chen XH, Liu J, Zhong JT, Zhou SH, Fan J. Effect of GLUT1 Inhibition and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells Under Hypoxic and Low-Glucose Conditions. Onco Targets Ther 2021; 14:3069-3081. [PMID: 34007184 PMCID: PMC8124017 DOI: 10.2147/ott.s300423] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/23/2021] [Indexed: 11/27/2022] Open
Abstract
Background Enhanced glucose uptake and autophagy are means by which cells adapt to stressful microenvironments. In this study, we investigated the roles of glucose transporter-1 (GLUT-1) and autophagy in laryngeal carcinoma stem cells under hypoxic and low-glucose conditions. Materials and Methods CD133-positive Tu212 laryngeal carcinoma stem cells were purified by magnetic-activated cell sorting and subjected to hypoxic and/or low-glucose conditions. Proliferation was evaluated using a cell-counting kit and a clone-formation assay, and migration capability was measured through a Transwell assay. Autophagy was assessed using transmission electron microscopy. Gene silencing was monitored using shRNA technology and autophagy regulation was manipulated using rapamycin, 3-MA, or chloroquine. Gene expression levels were evaluated by quantitative reverse transcription-polymerase chain reaction and protein levels were assessed via Western blotting. Results Compared to CD133-negative cells, CD133-positive cells showed increased proliferation and migration capabilities, and reduced apoptosis, under hypoxic or low-glucose conditions. CD133-positive cells also showed increased expression of GLUT-1 and autophagy activity. Finally, GLUT-1 knockdown or autophagy inhibition reduced the proliferation and migration of CD133-positive laryngeal carcinoma stem cells. Conclusion Enhanced glucose uptake and autophagy maintain the tumor behaviors of CD133-positive laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.
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Affiliation(s)
- Xiao-Hong Chen
- Department of Otolaryngology, The Second Hospital of Jiaxing (The Second Affiliated Hospital, Jiaxing University), Jiaxing City, Zhejiang Province, 314000, People's Republic of China
| | - Jia Liu
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiang-Tao Zhong
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Shui-Hong Zhou
- Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jun Fan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, People's Republic of China
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Guo C, Gao C, Lv X, Zhao D, Greenaway FT, Hao L, Tian Y, Liu S, Sun M. CRKL promotes hepatocarcinoma through enhancing glucose metabolism of cancer cells via activating PI3K/Akt. J Cell Mol Med 2021; 25:2714-2724. [PMID: 33523562 PMCID: PMC7933966 DOI: 10.1111/jcmm.16303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/05/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022] Open
Abstract
Abnormal glucose metabolism may contribute to cancer progression. As a member of the CRK (v-crk sarcoma virus CT10 oncogene homologue) adapter protein family, CRKL (CRK-like) associated with the development and progression of various tumours. However, the exact role and underlying mechanism of CRKL on energy metabolism remain unknown. In this study, we investigated the effect of CRKL on glucose metabolism of hepatocarcinoma cells. CRKL and PI3K were found to be overexpressed in both hepatocarcinoma cells and tissues; meanwhile, CRKL up-regulation was positively correlated with PI3K up-regulation. Functional investigations revealed that CRKL overexpression promoted glucose uptake, lactate production and glycogen synthesis of hepatocarcinoma cells by up-regulating glucose transporters 1 (GLUT1), hexokinase II (HKII) expression and down-regulating glycogen synthase kinase 3β (GSK3β) expression. Mechanistically, CRKL promoted glucose metabolism of hepatocarcinoma cells via enhancing the CRKL-PI3K/Akt-GLUT1/HKII-glucose uptake, CRKL-PI3K/Akt-HKII-glucose-lactate production and CRKL-PI3K/Akt-Gsk3β-glycogen synthesis. We demonstrate CRKL facilitates HCC malignancy via enhancing glucose uptake, lactate production and glycogen synthesis through PI3K/Akt pathway. It provides interesting fundamental clues to CRKL-related carcinogenesis through glucose metabolism and offers novel therapeutic strategies for hepatocarcinoma.
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Affiliation(s)
- Chunmei Guo
- Department of BiotechnologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | - Chao Gao
- Department of BiotechnologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
- Present address:
College of Medical Laboratory Science and Technology, Harbin Medical University (Daqing)DaqingChina
| | - Xinxin Lv
- Department of BiotechnologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | - Dongting Zhao
- Department of BiotechnologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | | | - Lihong Hao
- Department of Histology and EmbryologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | - Yuxiang Tian
- Department of BiochemistryCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | - Shuqing Liu
- Department of BiochemistryCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
| | - Ming‐Zhong Sun
- Department of BiotechnologyCollege of Basic Medical SciencesDalian Medical UniversityDalianChina
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Chen X, Zhao Y, Gao Y, Qi Y, Du J. Outcomes in hepatocellular carcinoma patients undergoing sorafenib treatment: toxicities, cellular oxidative stress, treatment adherence, and quality of life: Erratum. Anticancer Drugs 2021; 32:345-364. [PMID: 33417326 DOI: 10.1097/cad.0000000000001029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Xiaotong Chen
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yunshuo Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Yanfeng Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Yuanming Qi
- School of Life Sciences, Zhengzhou University, Zhengzhou
| | - Jiangfeng Du
- School of Life Sciences, Zhengzhou University, Zhengzhou
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45
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Yang L, Pei L, Yi J. LINC00839 Regulates Proliferation, Migration, Invasion, Apoptosis and Glycolysis in Neuroblastoma Cells Through miR-338-3p/GLUT1 Axis. Neuropsychiatr Dis Treat 2021; 17:2027-2040. [PMID: 34188473 PMCID: PMC8232867 DOI: 10.2147/ndt.s309467] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 05/27/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are related to the development and treatment of neuroblastoma. The lncRNA LINC00839 is dysregulated in neuroblastoma, while its function and mechanism in neuroblastoma development remain largely unclear. METHODS The tumor and adjacent noncancerous tissues were collected from 48 neuroblastoma patients. LINC00839, glucose transporter 1 (GLUT1) and microRNA-338-3p (miR-338-3p) abundances were examined via quantitative reverse transcription polymerase chain reaction or Western blot. Cell proliferation, apoptosis, migration, invasion and glycolysis were assessed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing, transwell, glucose uptake and lactate production. The target relationship of miR-338-3p and LINC00839 or GLUT1 was tested via dual-luciferase reporter analysis and RNA immunoprecipitation. The function of LINC00839 on neuroblastoma cell growth in vivo was tested via a xenograft model. RESULTS LINC00839 and GLUT1 abundances were increased in neuroblastoma tissues and cell lines. The high expression of LINC00839 and GLUT1 indicated the lower overall survival. LINC00839 interference constrained neuroblastoma cell proliferation, migration, invasion and glycolysis, and facilitated apoptosis. GLUT1 overexpression or miR-338-3p knockdown could mitigate the influence of LINC00839 silence on neuroblastoma cell processes. LINC00839 could regulate GLUT1 expression via miR-338-3p. LINC00839 knockdown reduced neuroblastoma cell growth in xenograft model. CONCLUSION LINC00839 silence repressed neuroblastoma cell proliferation, migration, invasion and glycolysis and promoted apoptosis via regulating miR-338-3p/GLUT1 axis.
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Affiliation(s)
- Lixia Yang
- Department of Neurology, The First People's Hospital of Jingmen Affiliated to Hubei Minzu University, Jingmen, 434000, People's Republic of China
| | - Liangyan Pei
- Department of Neurology, The First People's Hospital of Jingmen Affiliated to Hubei Minzu University, Jingmen, 434000, People's Republic of China
| | - Jilong Yi
- Department of Neurology, The First People's Hospital of Jingmen Affiliated to Hubei Minzu University, Jingmen, 434000, People's Republic of China
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Tilekar K, Upadhyay N, Iancu CV, Pokrovsky V, Choe JY, Ramaa CS. Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188457. [PMID: 33096154 PMCID: PMC7704680 DOI: 10.1016/j.bbcan.2020.188457] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.
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Affiliation(s)
- Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Cristina V. Iancu
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - Vadim Pokrovsky
- Laboratory of Combined Therapy, N.N. Blokhin Cancer Research Center, Moscow, Russia
- Department of Biochemistry, People’s Friendship University, Moscow, Russia
| | - Jun-yong Choe
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, North Carolina, USA
| | - C. S. Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai, Maharashtra, India
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Wang C, Gao X, Wang F, Guan W, Dou H, Xu G. Effect of Starvation in Reversing Cancer Chemoresistance Based on Drug-Resistance Detection by Dextran Nanoparticles. Int J Nanomedicine 2020; 15:9255-9264. [PMID: 33244234 PMCID: PMC7685360 DOI: 10.2147/ijn.s283430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/24/2020] [Indexed: 12/22/2022] Open
Abstract
Introduction Chemoresistance leads to chemotherapy failure in patients with cancer. Multidrug resistance (MDR) in cancer is mainly caused by the high expression of P-glycoprotein encoded by the MDR1 gene, which is an ATP-dependent protease. Keeping the stronger invasion and migration abilities of chemoresistant cells in cancer also requires more ATP consumption. Herein, we aimed to reverse resistance by reducing the glucose supply in the cellular environment. Methods A starvation approach in reversing chemoresistance was applied, which was implemented through preparing fluorescent dextran-based nanoparticles to detect the proportion of chemoresistant cells in the chemoresistant/chemosensitive cell mixture after cells cultured in a low-glucose condition. Results Chemoresistant cells had higher glucose consumption with higher ATPase expression and stronger glucose dependence compared to chemosensitive cells. Moreover, cancer cells cultured in a low-glucose condition reduced the proportion of chemoresistant cells. Conclusion Starvation therapy can be used as a new method to reverse drug resistance in cancer.
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Affiliation(s)
- Chenglong Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, People's Republic of China
| | - Xuzhu Gao
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, People's Republic of China
| | - Fanchen Wang
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, People's Republic of China
| | - Wencai Guan
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, People's Republic of China
| | - Hongjing Dou
- The State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Guoxiong Xu
- Research Center for Clinical Medicine, Jinshan Hospital, Fudan University, Shanghai 201508, People's Republic of China
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Tilekar K, Upadhyay N, Hess JD, Macias LH, Mrowka P, Aguilera RJ, Meyer-Almes FJ, Iancu CV, Choe JY, Ramaa CS. Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential. Eur J Med Chem 2020; 202:112603. [PMID: 32634629 PMCID: PMC7451030 DOI: 10.1016/j.ejmech.2020.112603] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/14/2020] [Accepted: 06/18/2020] [Indexed: 12/24/2022]
Abstract
Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital role in tumor cell survival and are overexpressed in various cancers. GLUT1, the most overexpressed GLUT in many cancers, is emerging as a promising anti-cancer target. To develop GLUT1 inhibitors, we rationally designed, synthesized, structurally characterized, and biologically evaluated in-vitro and in-vivo a novel series of furyl-2-methylene thiazolidinediones (TZDs). Among 25 TZDs tested, F18 and F19 inhibited GLUT1 most potently (IC50 11.4 and 14.7 μM, respectively). F18 was equally selective for GLUT4 (IC50 6.8 μM), while F19 was specific for GLUT1 (IC50 152 μM in GLUT4). In-silico ligand docking studies showed that F18 interacted with conserved residues in GLUT1 and GLUT4, while F19 had slightly different interactions with the transporters. In in-vitro antiproliferative screening of leukemic/lymphoid cells, F18 was most lethal to CEM cells (CC50 of 1.7 μM). Flow cytometry analysis indicated that F18 arrested cell cycle growth in the subG0-G1 phase and lead to cell death due to necrosis and apoptosis. Western blot analysis exhibited alterations in cell signaling proteins, consistent with cell growth arrest and death. In-vivo xenograft study in a CEM model showed that F18 impaired tumor growth significantly.
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Affiliation(s)
- Kalpana Tilekar
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Neha Upadhyay
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, Maharashtra, India
| | - Jessica D Hess
- The Cytometry, Screening and Imaging Core Facility & Border Biomedical Research Center & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Lucasantiago Henze Macias
- The Cytometry, Screening and Imaging Core Facility & Border Biomedical Research Center & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Piotr Mrowka
- Department of Biophysics and Human Physiology, Medical University of Warsaw, Chalubinskiego, Warsaw, Poland
| | - Renato J Aguilera
- The Cytometry, Screening and Imaging Core Facility & Border Biomedical Research Center & Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
| | - Franz-Josef Meyer-Almes
- Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Darmstadt, Germany
| | - Cristina V Iancu
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, NC, USA
| | - Jun-Yong Choe
- East Carolina Diabetes and Obesity Institute, Department of Chemistry, East Carolina University, Greenville, NC, USA; Department of Biochemistry and Molecular Biology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
| | - C S Ramaa
- Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, Maharashtra, India.
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Li ZY, Shi YL, Liang GX, Yang J, Zhuang SK, Lin JB, Ghodbane A, Tam MS, Liang ZJ, Zha ZG, Zhang HT. Visualization of GLUT1 Trafficking in Live Cancer Cells by the Use of a Dual-Fluorescence Reporter. ACS OMEGA 2020; 5:15911-15921. [PMID: 32656411 PMCID: PMC7345384 DOI: 10.1021/acsomega.0c01054] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/15/2020] [Indexed: 05/07/2023]
Abstract
Glucose metabolism is an essential process for energy production and cell survival for both normal and abnormal cellular metabolism. Several glucose transporter/solute carrier 2A (GLUT/SLC2A) superfamily members, including glucose transporter 1 (GLUT1), have been shown to mediate the cellular uptake of glucose in diverse cell types. GLUT1-mediated glucose uptake is a transient and rapid process; thus, the real-time monitoring of GLUT1 trafficking is pivotal for a better understanding of GLUT1 expression and GLUT1-dependent glucose uptake. In the present study, we established a rapid and effective method to visualize the trafficking of GLUT1 between the plasma membrane (PM) and endolysosomal system in live cells using an mCherry-EGFP-GLUT1 tandem fluorescence tracing system. We found that GLUT1 localized at the PM exhibited both red (mCherry) and green (EGFP) fluorescence (yellow when overlapping). However, a significant increase in red punctate fluorescence (mCherry is resistant to acidic pH), but not green fluorescence (EGFP is quenched by acidic pH), was observed upon glucose deprivation, indicating that the mCherry-EGFP-GLUT1 functional protein was trafficked to the acidic endolysosomal system. Besides, we were able to calculate the relative ratio of mCherry to EGFP by quantification of the translocation coefficient, which can be used as a readout for GLUT1 internalization and subsequent lysosomal degradation. Two mutants, mCherry-EGFP-GLUT1-S226D and mCherry-EGFP-GLUT1-ΔC4, were also constructed, which indirectly confirmed the specificity of mCherry-EGFP-GLUT1 for monitoring GLUT1 trafficking. By using a series of endosomal (Rab5, Rab7, and Rab11) and lysosomal markers, we were able to define a model of GLUT1 trafficking in live cells in which upon glucose deprivation, GLUT1 dissociates from the PM and experiences a pH gradient from 6.8-6.1 in the early endosomes to 6.0-4.8 in the late endosomes and finally pH 4.5 in lysosomes, which is appropriate for degradation. In addition, our proof-of-concept study indicated that the pmCherry-EGFP-GLUT1 tracing system can accurately reflect endogenous changes in GLUT1 in response to treatment with the small molecule, andrographolide. Since targeting GLUT1 expression and GLUT1-dependent glucose metabolism is a promising therapeutic strategy for diverse types of cancers and certain other glucose addiction diseases, our study herein indicates that pmCherry-EGFP-GLUT1 can be utilized as a biosensor for GLUT1-dependent functional studies and potential small molecule screening.
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Affiliation(s)
- Zhen-Yan Li
- Institute of Orthopedic Diseases and Department
of Bone and Joint Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
| | - Yu-Ling Shi
- Department of Orthopedics,
the Third Affiliated Hospital, Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Guo-Xiong Liang
- Department of Pharmacy, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, China
| | - Jie Yang
- Institute of Orthopedic Diseases and Department
of Bone and Joint Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
| | - Song-Kuan Zhuang
- State Key Laboratory
of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
| | - Jie-Bin Lin
- Department of Orthopedics,
the Third Affiliated Hospital, Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Abdelmoumin Ghodbane
- Institute of Orthopedic Diseases and Department
of Bone and Joint Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
| | - Man-Seng Tam
- IAN WO Medical Center, Macao Special
Administrative Region, Macao 999078, China
| | - Zu-Jian Liang
- Department of Orthopedics,
the Third Affiliated Hospital, Guangzhou
University of Chinese Medicine, Guangzhou, Guangdong 510405, China
- . Phone: 86-13751876166
| | - Zhen-Gang Zha
- Institute of Orthopedic Diseases and Department
of Bone and Joint Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
| | - Huan-Tian Zhang
- Institute of Orthopedic Diseases and Department
of Bone and Joint Surgery, the First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, China
- . Phone: 86-13802800152
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Zhang S, Lu Y, Liu Z, Li X, Wang Z, Cai Z. Identification Six Metabolic Genes as Potential Biomarkers for Lung Adenocarcinoma. J Comput Biol 2020; 27:1532-1543. [PMID: 32298601 DOI: 10.1089/cmb.2019.0454] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Metabolic genes have been reported to act as crucial roles in tumor progression. Lung adenocarcinoma (LUAD) is one of the most common cancers worldwide. This study aimed to predict the potential mechanism and novel markers of metabolic signature in LUAD. The gene expression profiles and the clinical parameters were obtained from The Cancer Genome Atlas-Lung adenocarcinoma (TCGA-LUAD) and Gene Expression Omnibus data set (GSE72094). A total of 105 differentially expressed metabolic genes of intersect expression in TCGA-LUAD and GSE72094 were screened by R language. Univariate Cox regression model found 18 survival-related genes and then the least absolute shrinkage and selection operator model was successfully constructed. Six significant genes prognostic model was validated though independent prognosis analysis. The model revealed high values for prognostic biomarkers by time-dependent receiver operating characteristic (ROC) analysis, risk score, Heatmap, and nomogram. In addition, Gene Set Enrichment Analysis showed that multiplex metabolism pathways correlated with LUAD. Furthermore, we found the six genes aberrantly expressed in LUAD samples. Our study showed that metabolism pathways play important roles in LUAD progression. The six metabolic genes could predict potential prognostic and diagnostic biomarkers in LUAD.
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Affiliation(s)
- Shusen Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Respiratory and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Yuanyuan Lu
- Department of Anesthesiology, and Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Zhongxin Liu
- Department of Pathology, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Xiaopeng Li
- Department of Neurosurgery, Handan First Hospital, Handan, China
| | - Zhihua Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, China
| | - Zhigang Cai
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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