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Pan Z, Liu Y, Li H, Qiu H, Zhang P, Li Z, Wang X, Tian Y, Feng Z, Zhu S, Wang X. The role and mechanism of aerobic glycolysis in nasopharyngeal carcinoma. PeerJ 2025; 13:e19213. [PMID: 40191756 PMCID: PMC11971989 DOI: 10.7717/peerj.19213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
This review delves into the pivotal role and intricate mechanisms of aerobic glycolysis in nasopharyngeal carcinoma (NPC). NPC, a malignancy originating from the nasopharyngeal epithelium, displays distinct geographical and clinical features. The article emphasizes the significance of aerobic glycolysis, a pivotal metabolic alteration in cancer cells, in NPC progression. Key enzymes such as hexokinase 2, lactate dehydrogenase A, phosphofructokinase 1, and pyruvate kinase M2 are discussed for their regulatory functions in NPC glycolysis through signaling pathways like PI3K/Akt and mTOR. Further, the article explores how oncogenic signaling pathways and transcription factors like c-Myc and HIF-1α modulate aerobic glycolysis, thereby affecting NPC's proliferation, invasion, metastasis, angiogenesis, and immune evasion. By elucidating these mechanisms, the review aims to advance research and clinical practice in NPC, informing the development of targeted therapeutic strategies that enhance treatment precision and reduce side effects. Overall, this review offers a broad understanding of the multifaceted role of aerobic glycolysis in NPC and its potential impact on therapeutic outcomes.
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Affiliation(s)
- Zhiyong Pan
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Yuyi Liu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Hui Li
- Department of Ophthalmology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Huisi Qiu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Pingmei Zhang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Zhiying Li
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Xinyu Wang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Yuxiao Tian
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Zhengfu Feng
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Song Zhu
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
| | - Xin Wang
- Department of Radiotherapy, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, Guangdong, China
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Zarrella S, Miranda MR, Covelli V, Restivo I, Novi S, Pepe G, Tesoriere L, Rodriquez M, Bertamino A, Campiglia P, Tecce MF, Vestuto V. Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer. Metabolites 2025; 15:221. [PMID: 40278350 PMCID: PMC12029571 DOI: 10.3390/metabo15040221] [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: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.
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Affiliation(s)
- Salvatore Zarrella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Maria Rosaria Miranda
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Verdiana Covelli
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Ignazio Restivo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Sara Novi
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Giacomo Pepe
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Luisa Tesoriere
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Manuela Rodriquez
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
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Xiang J, Fan L, Li H, Song Q, Jin Y, He R, Pan X, Wang D. Molecular disturbances and thyroid gland dysfunction in rats chronically exposed to a high dose of NaAsO₂: Insights from proteomic and phosphoproteomic analyses. JOURNAL OF HAZARDOUS MATERIALS 2025; 484:136746. [PMID: 39637814 DOI: 10.1016/j.jhazmat.2024.136746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 11/30/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
Arsenic is a ubiquitous hazardous metalloid that poses a significant threat to human health. Although researchers have investigated the detrimental effects of arsenic on the thyroid, a comprehensive exploration of its toxicological impact and underlying molecular mechanisms remains to be conducted. Both this study and our previous reports demonstrated that chronic exposure to sodium arsenite (NaAsO2) results in histological impairment and dysfunction of the thyroid glands in Sprague-Dawley (SD) rats. Proteomic and phosphoproteomic analyses were performed to investigate the molecular mechanisms underlying the effects of chronic NaAsO2 exposure on thyroid function in SD rats. NaAsO2 disrupts the synthesis of thyroid hormones (THs) and alters the expression of the THs-synthesizing enzyme dual oxidase 2. In addition, oxidative phosphorylation, the AMP-activated protein kinase signaling pathway, central carbon metabolism in cancer, cysteine and methionine metabolism, cellular response to heat stress, and protein processing in the endoplasmic reticulum were upregulated, whereas glutathione metabolism was downregulated. In conclusion, this study revealed thyroid damage in SD rats induced by chronic NaAsO2 exposure and elucidated the disrupted molecular pathways, thereby providing novel insights into the molecular mechanisms underlying arsenic exposure and its impact on thyroid function.
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Affiliation(s)
- Jie Xiang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Lili Fan
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Hui Li
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Qian Song
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Ying Jin
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Rui He
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Xueli Pan
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China
| | - Dapeng Wang
- Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang 561113, Guizhou, PR China; Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang 561113, Guizhou, PR China.
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Shafi S, Khan MA, Ahmad J, Rabbani SA, Singh S, Najmi AK. Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach. Curr Drug Targets 2025; 26:109-131. [PMID: 39377414 DOI: 10.2174/0113894501335877240926101134] [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: 06/27/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 10/09/2024]
Abstract
Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.
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Affiliation(s)
- Sadat Shafi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Mohammad Ahmed Khan
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Javed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Najran University, Kingdom of Saudi Arabia (KSA)
| | - Syed Arman Rabbani
- Department of Clinical Pharmacy and Pharmacology, Ras Al Khaimah College of Pharmacy, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah, United Arab Emirates
| | - Shailja Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Abul Kalam Najmi
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
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Dyachenko EI, Bel’skaya LV. Transmembrane Amino Acid Transporters in Shaping the Metabolic Profile of Breast Cancer Cell Lines: The Focus on Molecular Biological Subtype. Curr Issues Mol Biol 2024; 47:4. [PMID: 39852119 PMCID: PMC11763447 DOI: 10.3390/cimb47010004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/26/2025] Open
Abstract
Amino acid metabolism in breast cancer cells is unique for each molecular biological subtype of breast cancer. In this review, the features of breast cancer cell metabolism are considered in terms of changes in the amino acid composition due to the activity of transmembrane amino acid transporters. In addition to the main signaling pathway PI3K/Akt/mTOR, the activity of the oncogene c-Myc, HIF, p53, GATA2, NF-kB and MAT2A have a direct effect on the amino acid metabolism of cancer cells, their growth and proliferation, as well as the maintenance of homeostatic equilibrium. A distinctive feature of luminal subtypes of breast cancer from TNBC is the ability to perform gluconeogenesis. Breast cancers with a positive expression of the HER2 receptor, in contrast to TNBC and luminal A subtype, have a distinctive active synthesis and consumption of fatty acids. It is interesting to note that amino acid transporters exhibit their activity depending on the pH level inside the cell. In the most aggressive forms of breast cancer or with the gradual progression of the disease, pH will also change, which will directly affect the metabolism of amino acids. Using the cell lines presented in this review, we can trace the characteristic features inherent in each of the molecular biological subtypes of breast cancer and develop the most optimal therapeutic targets.
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Affiliation(s)
| | - Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
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John P, Sudandiradoss C. Structure, function and stability analysis on potential deleterious mutation ensemble in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for early detection of LUAD. Life Sci 2024; 358:123127. [PMID: 39427874 DOI: 10.1016/j.lfs.2024.123127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 09/27/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024]
Abstract
AIMS Lung adenocarcinoma (LUAD) is the most prominent histological subtype among the lung cancer which is a leading cause in the cancer mortality rate. High mutational and glycolytic rates are the major reported alterations in the lung cancer. Here in our study we are elucidating the structural and functional role of key glycolytic enzyme Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and associated SNPs in LUAD progression. MATERIALS AND METHODS Our gene expression analysis reveals high expression of GAPDH in the LUAD. In silico tools and analysis were used for the identification and characterization of the deleterious SNPs. Molecular Docking and dynamics simulations (MDS) studies characterized the structural consequences of prioritized deleterious mutations. KEY FINDINGS The sequence based analysis to identify SNPs in GAPDH resulted in 28 deleterious SNPs and 6 SNPs among them showed deleterious and damaging effect. The structural based analysis resulted in 2 stabilizing SNPs of rs ids rs11549328 (D39Y) and rs200102749 (S51Y) in the conserved domain. The IDR and PTM analysis of the GAPDH sequence resulted an IDR region from 191 to 194 positions with an IDR score of 0.511, 0.520, 0.517 and 0.503 with the PTM modifications. SIGNIFICANCE The identified deleterious SNPs (D39Y and S51Y) fall in the functional and conserved domain of GAPDH. In addition, the existence of PTMs within the IDR region of the GAPDH may contribute to its enhanced glycolytic activity in LUAD. The results of our study provide potential background deleterious mutants the pathological aspect of GAPDH in LUAD progression.
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Affiliation(s)
- Pearl John
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu 632014, India
| | - C Sudandiradoss
- Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu 632014, India.
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Zhang J, Chen M, Yang Y, Liu Z, Guo W, Xiang P, Zeng Z, Wang D, Xiong W. Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy. J Cell Physiol 2024; 239:e31349. [PMID: 38946173 DOI: 10.1002/jcp.31349] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 06/08/2024] [Accepted: 06/14/2024] [Indexed: 07/02/2024]
Abstract
Amino acids are essential building blocks for proteins, crucial energy sources for cell survival, and key signaling molecules supporting the resistant growth of tumor cells. In tumor cells, amino acid metabolic reprogramming is characterized by the enhanced uptake of amino acids as well as their aberrant synthesis, breakdown, and transport, leading to immune evasion and malignant progression of tumor cells. This article reviews the altered amino acid metabolism in tumor cells and its impact on tumor microenvironment, and also provides an overview of the current clinical applications of amino acid metabolism. Innovative drugs targeting amino acid metabolism hold great promise for precision and personalized cancer therapy.
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Affiliation(s)
- Jiarong Zhang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Mingjian Chen
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Yuxin Yang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Ziqi Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Wanni Guo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Pingjuan Xiang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Dan Wang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
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Jemal M, Getinet M, Amare GA, Tegegne BA, Baylie T, Mengistu EF, Osman EE, Chura Waritu N, Adugna A. Non-metabolic enzyme function of pyruvate kinase M2 in breast cancer. Front Oncol 2024; 14:1450325. [PMID: 39411137 PMCID: PMC11473492 DOI: 10.3389/fonc.2024.1450325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Breast cancer (BC) is a prevalent malignant tumor in women, and its incidence has been steadily increasing in recent years. Compared with other types of cancer, it has the highest mortality and morbidity rates in women. So, it is crucial to investigate the underlying mechanisms of BC development and identify specific therapeutic targets. Pyruvate kinase M2 (PKM2), an important metabolic enzyme in glycolysis, has been found to be highly expressed in BC. It can also move to the nucleus and interact with various transcription factors and proteins, including hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3), β-catenin, cellular-myelocytomatosis oncogene (c-Myc), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mammalian sterile 20-like kinase 1 (MST1). This interaction leads to non-metabolic functions that control the cell cycle, proliferation, apoptosis, migration, invasion, angiogenesis, and tumor microenvironment in BC. This review provides an overview of the latest advancements in understanding the interactions between PKM2 and different transcription factors and proteins that influence the initiation and progression of BC. It also examined how natural drugs and noncoding RNAs affect various biological processes in BC cells through the regulation of the non-metabolic enzyme functions of PKM2. The findings provide valuable insights for improving the prognosis and developing targeted therapies for BC in the coming years.
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Affiliation(s)
- Mohammed Jemal
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Mamaru Getinet
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Bantayehu Addis Tegegne
- Department of Pharmacy, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Temesgen Baylie
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enyew Fenta Mengistu
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Enatnesh Essa Osman
- Department of Biomedical Science, School of Medicine, Debre Markos University, Debre Markos, Ethiopia
| | - Nuredin Chura Waritu
- Department of Biomedical Sciences, School of Medicine, Wolaita Sodo University, Wolaita Sodo, Ethiopia
| | - Adane Adugna
- Department of Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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Garcia-Del Rio DF, Derhourhi M, Bonnefond A, Leblanc S, Guilloy N, Roucou X, Eyckerman S, Gevaert K, Salzet M, Cardon T. Deciphering the ghost proteome in ovarian cancer cells by deep proteogenomic characterization. Cell Death Dis 2024; 15:712. [PMID: 39349928 PMCID: PMC11442847 DOI: 10.1038/s41419-024-07046-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024]
Abstract
Proteogenomics is becoming a powerful tool in personalized medicine by linking genomics, transcriptomics and mass spectrometry (MS)-based proteomics. Due to increasing evidence of alternative open reading frame-encoded proteins (AltProts), proteogenomics has a high potential to unravel the characteristics, variants, expression levels of the alternative proteome, in addition to already annotated proteins (RefProts). To obtain a broader view of the proteome of ovarian cancer cells compared to ovarian epithelial cells, cell-specific total RNA-sequencing profiles and customized protein databases were generated. In total, 128 RefProts and 30 AltProts were identified exclusively in SKOV-3 and PEO-4 cells. Among them, an AltProt variant of IP_715944, translated from DHX8, was found mutated (p.Leu44Pro). We show high variation in protein expression levels of RefProts and AltProts in different subcellular compartments. The presence of 117 RefProt and two AltProt variants was described, along with their possible implications in the different physiological/pathological characteristics. To identify the possible involvement of AltProts in cellular processes, cross-linking-MS (XL-MS) was performed in each cell line to identify AltProt-RefProt interactions. This approach revealed an interaction between POLD3 and the AltProt IP_183088, which after molecular docking, was placed between POLD3-POLD2 binding sites, highlighting its possibility of the involvement in DNA replication and repair.
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Affiliation(s)
- Diego Fernando Garcia-Del Rio
- Univ. Lille, Inserm, CHU Lille, U1192, Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, F-59000, Lille, France
- VIB Center for Medical Biotechnology, VIB, Ghent, 9052, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, 9052, Belgium
| | - Mehdi Derhourhi
- Université de Lille, Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France University of Lille, Lille, France
| | - Amelie Bonnefond
- Université de Lille, Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France University of Lille, Lille, France
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Sébastien Leblanc
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, J1E4K8, Canada
| | - Noé Guilloy
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, J1E4K8, Canada
| | - Xavier Roucou
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, J1E4K8, Canada
| | - Sven Eyckerman
- VIB Center for Medical Biotechnology, VIB, Ghent, 9052, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, 9052, Belgium
| | - Kris Gevaert
- VIB Center for Medical Biotechnology, VIB, Ghent, 9052, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, 9052, Belgium
| | - Michel Salzet
- Univ. Lille, Inserm, CHU Lille, U1192, Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, F-59000, Lille, France.
| | - Tristan Cardon
- Univ. Lille, Inserm, CHU Lille, U1192, Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, F-59000, Lille, France.
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Vásquez Martínez IP, Pérez-Campos E, Pérez-Campos Mayoral L, Cruz Luis HI, Pina Canseco MDS, Zenteno E, Bazán Salinas IL, Martínez Cruz M, Pérez-Campos Mayoral E, Hernández-Huerta MT. O-GlcNAcylation: Crosstalk between Hemostasis, Inflammation, and Cancer. Int J Mol Sci 2024; 25:9896. [PMID: 39337387 PMCID: PMC11432004 DOI: 10.3390/ijms25189896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc, O-GlcNAcylation) is a post-translational modification of serine/threonine residues of proteins. Alterations in O-GlcNAcylation have been implicated in several types of cancer, regulation of tumor progression, inflammation, and thrombosis through its interaction with signaling pathways. We aim to explore the relationship between O-GlcNAcylation and hemostasis, inflammation, and cancer, which could serve as potential prognostic tools or clinical predictions for cancer patients' healthcare and as an approach to combat cancer. We found that cancer is characterized by high glucose demand and consumption, a chronic inflammatory state, a state of hypercoagulability, and platelet hyperaggregability that favors thrombosis; the latter is a major cause of death in these patients. Furthermore, we review transcription factors and pathways associated with O-GlcNAcylation, thrombosis, inflammation, and cancer, such as the PI3K/Akt/c-Myc pathway, the nuclear factor kappa B pathway, and the PI3K/AKT/mTOR pathway. We also review infectious agents associated with cancer and chronic inflammation and potential inhibitors of cancer cell development. We conclude that it is necessary to approach both the diagnosis and treatment of cancer as a network in which multiple signaling pathways are integrated, and to search for a combination of potential drugs that regulate this signaling network.
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Affiliation(s)
- Itzel Patricia Vásquez Martínez
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Eduardo Pérez-Campos
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Laura Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Holanda Isabel Cruz Luis
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María del Socorro Pina Canseco
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Edgar Zenteno
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico;
| | - Irma Leticia Bazán Salinas
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Margarito Martínez Cruz
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Eduardo Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María Teresa Hernández-Huerta
- National Council of Humanities, Sciences and Technologies (CONAHCYT), Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68120, Mexico
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Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol 2024; 15:1353787. [PMID: 39119332 PMCID: PMC11306065 DOI: 10.3389/fimmu.2024.1353787] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/04/2024] [Indexed: 08/10/2024] Open
Abstract
Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology, Department of Medical and Oncological Area, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy
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12
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Han B, Zhen F, Sun Y, Sun B, Wang HY, Liu W, Huang J, Liang X, Wang YR, Chen XS, Li SJ, Hu J. Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer. Cell Rep 2024; 43:114507. [PMID: 39003742 DOI: 10.1016/j.celrep.2024.114507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/29/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
The oxidative-stress-related protein Kelch-like ECH-associated protein 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification of proteins. However, the function of KEAP1 in breast cancer and its impact on the survival of patients with breast cancer remain unclear. Our study demonstrates that KEAP1, a positive prognostic factor, plays a crucial role in regulating cell proliferation, apoptosis, and cell cycle transition in breast cancer. We investigate the underlying mechanism using human tumor tissues, high-throughput detection technology, and a mouse xenograft tumor model. KEAP1 serves as a key regulator of cellular metabolism, the reprogramming of which is one of the hallmarks of tumorigenesis. KEAP1 has a significant effect on mitochondrial biogenesis and oxidative phosphorylation by regulating HSPA9 ubiquitination and degradation. These results suggest that KEAP1 could serve as a potential biomarker and therapeutic target in the treatment of breast cancer.
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Affiliation(s)
- Bing Han
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Fang Zhen
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Yue Sun
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Bin Sun
- Research Center for Pharmacoinformatics (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang Province 150081, China
| | - Hong-Yi Wang
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Wei Liu
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Jian Huang
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Xiao Liang
- Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang Province 150081, China
| | - Ya-Ru Wang
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China
| | - Xue-Song Chen
- Department of Oncology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, Heilongjiang Province 150001, China.
| | - Shui-Jie Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province 150081, China.
| | - Jing Hu
- Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China; Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education, Harbin, Heilongjiang Province 150081, China.
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13
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Arizmendi-Izazaga A, Navarro-Tito N, Jiménez-Wences H, Evaristo-Priego A, Priego-Hernández VD, Dircio-Maldonado R, Zacapala-Gómez AE, Mendoza-Catalán MÁ, Illades-Aguiar B, De Nova Ocampo MA, Salmerón-Bárcenas EG, Leyva-Vázquez MA, Ortiz-Ortiz J. Bioinformatics Analysis Reveals E6 and E7 of HPV 16 Regulate Metabolic Reprogramming in Cervical Cancer, Head and Neck Cancer, and Colorectal Cancer through the PHD2-VHL-CUL2-ELOC-HIF-1α Axis. Curr Issues Mol Biol 2024; 46:6199-6222. [PMID: 38921041 PMCID: PMC11202971 DOI: 10.3390/cimb46060370] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 06/06/2024] [Accepted: 06/15/2024] [Indexed: 06/27/2024] Open
Abstract
Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1β to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.
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Affiliation(s)
- Adán Arizmendi-Izazaga
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
| | - Hilda Jiménez-Wences
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
| | - Adilene Evaristo-Priego
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Víctor Daniel Priego-Hernández
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Roberto Dircio-Maldonado
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
| | - Ana Elvira Zacapala-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Miguel Ángel Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Mónica Ascención De Nova Ocampo
- Escuela Nacional de Medicina y Homeopatía, Programa Institucional de Biomedicina Molecular, Instituto Politécnico Nacional, Guillermo Massieu Helguera No. 239 Col. Fracc. La Escalera-Ticomán, Ciudad de Mexico C.P. 07320, Mexico;
| | - Eric Genaro Salmerón-Bárcenas
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México C.P. 07360, Mexico;
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (A.E.-P.); (V.D.P.-H.); (A.E.Z.-G.); (M.Á.M.-C.); (B.I.-A.)
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
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14
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Huang YH, Chiu LY, Tseng JS, Hsu KH, Chen CH, Sheu GT, Yang TY. Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor. Int J Mol Sci 2024; 25:616. [PMID: 38203787 PMCID: PMC10779050 DOI: 10.3390/ijms25010616] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/15/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these ABCB1-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.
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Affiliation(s)
- Yen-Hsiang Huang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Ling-Yen Chiu
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
| | - Jeng-Sen Tseng
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Kuo-Hsuan Hsu
- Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan;
| | - Chang-Han Chen
- Department of Applied Chemistry, Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou 545, Taiwan;
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Gwo-Tarng Sheu
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Tsung-Ying Yang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; (Y.-H.H.); (L.-Y.C.); (J.-S.T.)
- Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan
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15
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Guo Z, Zhang Y, Huang A, Ni Q, Zeng C. Phenylbutyrate and Dichloroacetate Enhance the Liquid-Stored Boar Sperm Quality via PDK1 and PDK3. Int J Mol Sci 2023; 24:17091. [PMID: 38069413 PMCID: PMC10707026 DOI: 10.3390/ijms242317091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/30/2023] [Accepted: 12/02/2023] [Indexed: 12/18/2023] Open
Abstract
Artificial insemination (AI) with liquid-stored semen is the most prevalent and efficient assisted reproduction technique in the modern pork industry. Pyruvate dehydrogenase complex component X (PDHX) was demonstrated to be associated with sperm metabolism and affected the boar sperm viability, motility, and fertility. Pyruvate Dehydrogenase Kinases (PDKs) are the key metabolic enzymes that regulate pyruvate dehydrogenase complex (PDHC) activity and also the conversion from glycolysis to oxidative phosphorylation. In the present study, two PDK inhibitors, Dichloroacetate (DCA) and Phenylbutyrate (4-PBA), were added to an extender and investigated to determine their regulatory roles in liquid-stored boar sperm at 17 °C. The results indicated that PDK1 and PDK3 were predominantly located at the head and flagella of the boar sperm. The addition of 2 mM DCA and 0.5 mM 4-PBA significantly enhanced the sperm motility, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), and ATP content. In addition, DCA and 4-PBA exerted their effects by inhibiting PDK1 and PDK3, respectively. In conclusion, DCA and 4-PBA were found to regulate the boar sperm metabolic activities via PDK1 and PDK3. These both can improve the quality parameters of liquid-stored boar sperm, which will help to improve and optimize liquid-stored boar semen after their addition in the extender.
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Affiliation(s)
- Zhihua Guo
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China; (Z.G.); (Y.Z.); (Q.N.)
- Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
| | - Yan Zhang
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China; (Z.G.); (Y.Z.); (Q.N.)
- Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
| | - Anqi Huang
- College of Life Science, Sichuan Agricultural University, Ya’an 625014, China;
| | - Qingyong Ni
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China; (Z.G.); (Y.Z.); (Q.N.)
- Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
| | - Changjun Zeng
- State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China; (Z.G.); (Y.Z.); (Q.N.)
- Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611134, China
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Song D, Zhang M, Duan C, Wei M, Xu D, An Y, Zhang L, Wang F, Feng M, Qian Z, Gao Q, Guo F. A machine learning-based integrated clinical model for predicting prognosis in atypical meningioma patients. Acta Neurochir (Wien) 2023; 165:4191-4201. [PMID: 37819396 DOI: 10.1007/s00701-023-05831-z] [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] [Received: 04/25/2023] [Accepted: 09/15/2023] [Indexed: 10/13/2023]
Abstract
PURPOSE Atypical meningioma (AM) recurs in up to half of patients after surgical resection and may require adjuvant therapy to improve patient prognosis. Various clinicopathological features have been shown to have prognostic implications in AM, but an integrated prediction model is lacking. Thus, in this study, we aimed to develop and validate an integrated prognostic model for AM. METHODS A retrospective cohort of 528 adult AM patients surgically treated at our institution were randomly assigned to a training or validation group in a 7:3 ratio. Sixteen baseline demographic, clinical, and pathological parameters, progression-free survival (PFS), and overall survival (OS) were analysed. Sixty-five combinations of machine learning (ML) algorithms were used for model training and validation to predict tumour recurrence and patient mortality. RESULTS The random survival forest (RSF) model was the best model for predicting recurrence and death. Primary or secondary tumour, Ki-67 index, extent of resection, tumour size, brain involvement, tumour necrosis, and age contributed significantly to the model. The C-index value of the RSF recurrence prediction model reached 0.8080. The AUCs for 1-, 3-, and 5-year PFS were 0.83, 0.82, and 0.86, respectively. The C-index value of the RSF death prediction model reached 0.8890. The AUCs for 3-year and 5-year OS were 0.88 and 0.89, respectively. CONCLUSION A high-performing integrated RSF predictive model for AM recurrence and patient mortality was proposed that may guide therapeutic decision-making and long-term monitoring.
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Affiliation(s)
- Dengpan Song
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Mingchu Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Chengcheng Duan
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Mingkun Wei
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Dingkang Xu
- Department of Neurosurgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan An
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Longxiao Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Fang Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Mengzhao Feng
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhihong Qian
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Qiang Gao
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Fuyou Guo
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe Road, Zhengzhou, 450001, Henan Province, China.
- International Joint Laboratory of Nervous System Malformations, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
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Lin X, Zhou W, Liu Z, Cao W, Lin C. Targeting cellular metabolism in head and neck cancer precision medicine era: A promising strategy to overcome therapy resistance. Oral Dis 2023; 29:3101-3120. [PMID: 36263514 DOI: 10.1111/odi.14411] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/17/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the most prevalent cancer worldwide, with the most severe impact on quality of life of patients. Despite the development of multimodal therapeutic approaches, the clinical outcomes of HNSCC are still unsatisfactory, mainly caused by relatively low responsiveness to treatment and severe drug resistance. Metabolic reprogramming is currently considered to play a pivotal role in anticancer therapeutic resistance. This review aimed to define the specific metabolic programs and adaptations in HNSCC therapy resistance. An extensive literature review of HNSCC was conducted via the PubMed including metabolic reprogramming, chemo- or immune-therapy resistance. Glucose metabolism, fatty acid metabolism, and amino acid metabolism are closely related to the malignant biological characteristics of cancer, anti-tumor drug resistance, and adverse clinical results. For HNSCC, pyruvate, lactate and almost all lipid categories are related to the occurrence and maintenance of drug resistance, and targeting amino acid metabolism can prevent tumor development and enhance the response of drug-resistant tumors to anticancer therapy. This review will provide a better understanding of the altered metabolism in therapy resistance of HNSCC and promote the development of new therapeutic strategies against HNSCC, thereby contribute to a more efficacious precision medicine.
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Affiliation(s)
- Xiaohu Lin
- Department of Oral Maxillofacial-Head and Neck Oncology, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Wenkai Zhou
- Department of Oral Maxillofacial-Head and Neck Oncology, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Zheqi Liu
- Department of Oral Maxillofacial-Head and Neck Oncology, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Wei Cao
- Department of Oral Maxillofacial-Head and Neck Oncology, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Jiao Tong University School of Nursing, Shanghai, China
| | - Chengzhong Lin
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- The 2nd Dental Center, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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18
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Chaba A, Fodil S, Lemiale V, Mariotte E, Valade S, Azoulay E, Zafrani L. Clinical Warburg effect in lymphoma patients admitted to intensive care unit. Ann Intensive Care 2023; 13:97. [PMID: 37796407 PMCID: PMC10555986 DOI: 10.1186/s13613-023-01192-z] [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: 07/20/2023] [Accepted: 09/20/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND The Warburg effect, characterized by elevated lactate levels without tissue hypoxia or shock, has been described in patients with aggressive lymphoproliferative malignancies. However, the clinical characteristics and long-term outcomes in this population remain poorly understood. METHODS We retrospectively analyzed 135 patients with aggressive lymphoproliferative malignancies admitted to the ICU between January 2017 and December 2022. Patients were classified into three groups: Clinical Warburg Effect (CWE), No Warburg with High Lactate level (NW-HL), and No Warburg with Normal Lactate level (NW-NL). Clinical characteristics and outcomes were compared between the groups and factors associated with 1-year mortality and CWE were identified using multivariable analyses. RESULTS Of the 135 patients, 46 (34%) had a CWE. This group had a higher proportion of Burkitt and T cell lymphomas, greater tumor burden, and more frequent bone and cerebral involvement than the other groups. At 1 year, 72 patients (53%) died, with significantly higher mortality in the CWE and NW-HL groups (70% each) than in the NW-NL group (38%). Factors independently associated with 1-year mortality were age [HR = 1.02 CI 95% (1.00-1.04)], total SOFA score at admission [HR = 1.19 CI 95% (1.12-1.25)], and CWE [HR = 3.87 CI 95% (2.13-7.02)]. The main factors associated with the CWE were tumor lysis syndrome [OR = 2.84 CI 95% (1.14-7.42)], bone involvement of the underlying malignancy [OR = 3.58 CI 95% (1.02-12.91)], the total SOFA score at admission [OR = 0.81 CI 95% (0.69-0.91)] and hypoglycemia at admission [OR = 14.90 CI 95% (5.42-47.18)]. CONCLUSION CWE is associated with a higher tumor burden and increased 1-year mortality compared to patients without this condition. Our findings underscore the importance of recognizing patients with CWE as a high-risk cohort, as their outcomes closely resemble those of individuals with lymphoma and shock, despite not requiring advanced organ support. Clinicians should recognize the urgency of managing these patients and consider early intervention to improve their prognosis.
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Affiliation(s)
- Anis Chaba
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - Sofiane Fodil
- Department of Hematology, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Virginie Lemiale
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - Eric Mariotte
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - Sandrine Valade
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France
| | - Elie Azoulay
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France
- University Paris Cité, Paris, France
| | - Lara Zafrani
- Medical Intensive Care Unit, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 1 Avenue Claude Vellefaux, 75010, Paris, France.
- University Paris Cité, Paris, France.
- INSERM, UMR 944, University Paris Cité, Paris, France.
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19
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Tarazi D, Maynes JT. Impact of Opioids on Cellular Metabolism: Implications for Metabolic Pathways Involved in Cancer. Pharmaceutics 2023; 15:2225. [PMID: 37765194 PMCID: PMC10534826 DOI: 10.3390/pharmaceutics15092225] [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: 08/01/2023] [Revised: 08/23/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
Opioid utilization for pain management is prevalent among cancer patients. There is significant evidence describing the many effects of opioids on cancer development. Despite the pivotal role of metabolic reprogramming in facilitating cancer growth and metastasis, the specific impact of opioids on crucial oncogenic metabolic pathways remains inadequately investigated. This review provides an understanding of the current research on opioid-mediated changes to cellular metabolic pathways crucial for oncogenesis, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS). The existing literature suggests that opioids affect energy production pathways via increasing intracellular glucose levels, increasing the production of lactic acid, and reducing ATP levels through impediment of OXPHOS. Opioids modulate pathways involved in redox balance which may allow cancer cells to overcome ROS-mediated apoptotic signaling. The majority of studies have been conducted in healthy tissue with a predominant focus on neuronal cells. To comprehensively understand the impact of opioids on metabolic pathways critical to cancer progression, research must extend beyond healthy tissue and encompass patient-derived cancer tissue, allowing for a better understanding in the context of the metabolic reprogramming already undergone by cancer cells. The current literature is limited by a lack of direct experimentation exploring opioid-induced changes to cancer metabolism as they relate to tumor growth and patient outcome.
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Affiliation(s)
- Doorsa Tarazi
- Department of Biochemistry, University of Toronto, Toronto, ON M5G 1A8, Canada;
- Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Jason T. Maynes
- Department of Biochemistry, University of Toronto, Toronto, ON M5G 1A8, Canada;
- Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
- Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON M5G 1E2, Canada
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20
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Kumar V, Stewart JH. Immunometabolic reprogramming, another cancer hallmark. Front Immunol 2023; 14:1125874. [PMID: 37275901 PMCID: PMC10235624 DOI: 10.3389/fimmu.2023.1125874] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/02/2023] [Indexed: 06/07/2023] Open
Abstract
Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best illustrated in the six hallmarks of the cancer: (1) the development of self-sufficient growth signals, (2) the emergence of clones that are resistant to apoptosis, (3) resistance to the antigrowth signals, (4) neo-angiogenesis, (5) the invasion of normal tissue or spread to the distant organs, and (6) limitless replicative potential. It also appears that non-resolving inflammation leads to the dysregulation of immune cell metabolism and subsequent cancer progression. The present article delineates immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis. We propose that targeting tumor immunometabolic reprogramming will lead to the design of novel immunotherapeutic approaches to cancer.
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Affiliation(s)
- Vijay Kumar
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
| | - John H. Stewart
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
- Louisiana State University- Louisiana Children’s Medical Center, Stanley S. Scott, School of Medicine, Louisiana State University Health Science Center (LSUHSC), New Orleans, LA, United States
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21
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Nunes-Xavier CE, Emaldi M, Mingo J, Øyjord T, Mælandsmo GM, Fodstad Ø, Errarte P, Larrinaga G, Llarena R, López JI, Pulido R. The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma. Sci Rep 2023; 13:7339. [PMID: 37147361 PMCID: PMC10162970 DOI: 10.1038/s41598-023-34087-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 04/24/2023] [Indexed: 05/07/2023] Open
Abstract
Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
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Affiliation(s)
- Caroline E Nunes-Xavier
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
| | - Maite Emaldi
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Janire Mingo
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Tove Øyjord
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Gunhild M Mælandsmo
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
- University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
| | - Peio Errarte
- Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Gorka Larrinaga
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Roberto Llarena
- Department of Urology, Cruces University Hospital, Barakaldo, Spain
| | - José I López
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
| | - Rafael Pulido
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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22
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The NRSF/REST transcription factor in hallmarks of cancer: From molecular mechanisms to clinical relevance. Biochimie 2023; 206:116-134. [PMID: 36283507 DOI: 10.1016/j.biochi.2022.10.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022]
Abstract
The RE-1 silencing transcription factor (REST), or neuron restrictive silencing factor (NRSF), was first identified as a repressor of neuronal genes in non-neuronal tissue. Interestingly, this transcription factor may act as a tumor suppressor or an oncogenic role in developing neuroendocrine and other tumors in patients. The hallmarks of cancer include six biological processes, including proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, inducing angiogenesis, and activating invasion and metastasis. In addition to two emerging hallmarks, the reprogramming of energy metabolism and evasion of the immune response are all implicated in the development of human tumors. It is essential to know the role of these processes as they will affect the outcome of alternatives for cancer treatment. Various studies in this review demonstrate that NRSF/REST affects the different hallmarks of cancer that could position NRSF/REST as an essential target in the therapy and diagnosis of certain types of cancer.
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23
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Verhoeff SR, Oosting SF, Elias SG, van Es SC, Gerritse SL, Angus L, Heskamp S, Desar IM, Menke-van der Houven van Oordt CW, van der Veldt AA, Arens AI, Brouwers AH, Eisses B, Mulders PF, Hoekstra OS, Zwezerijnen GJ, van der Graaf WT, Aarntzen EH, Oyen WJ, van Herpen CM. [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to Predict Watchful Waiting Duration in Patients with Metastatic Clear-cell Renal Cell Carcinoma. Clin Cancer Res 2023; 29:592-601. [PMID: 36394882 PMCID: PMC9890134 DOI: 10.1158/1078-0432.ccr-22-0921] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/11/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022]
Abstract
PURPOSE Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC. EXPERIMENTAL DESIGN Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. RESULTS The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). CONCLUSIONS In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.
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Affiliation(s)
- Sarah R. Verhoeff
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Sjoukje F. Oosting
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Sjoerd G. Elias
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Suzanne C. van Es
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Sophie L. Gerritse
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Oncology, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Lindsay Angus
- Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sandra Heskamp
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ingrid M.E. Desar
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Astrid A.M. van der Veldt
- Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Anne I.J. Arens
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Adrienne H. Brouwers
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bertha Eisses
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Peter F.A. Mulders
- Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Otto S. Hoekstra
- Department of Radiology and Nuclear Medicine, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gerben J.C. Zwezerijnen
- Department of Radiology and Nuclear Medicine, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Winette T.A. van der Graaf
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Erik H.J.G. Aarntzen
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Wim J.G. Oyen
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Radiology and Nuclear Medicine, Rijnstate, Arnhem, the Netherlands.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Carla M.L. van Herpen
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Corresponding Author: Carla M.L. van Herpen, Radboud University Nijmegen Medical Center, Nijmegen 6500 HB, the Netherlands. Phone: 312-4361-4038; Fax: 312-4361-5025; E-mail:
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24
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Priego-Hernández VD, Arizmendi-Izazaga A, Soto-Flores DG, Santiago-Ramón N, Feria-Valadez MD, Navarro-Tito N, Jiménez-Wences H, Martínez-Carrillo DN, Salmerón-Bárcenas EG, Leyva-Vázquez MA, Illades-Aguiar B, Alarcón-Romero LDC, Ortiz-Ortiz J. Expression of HIF-1α and Genes Involved in Glucose Metabolism Is Increased in Cervical Cancer and HPV-16-Positive Cell Lines. Pathogens 2022; 12:pathogens12010033. [PMID: 36678382 PMCID: PMC9865746 DOI: 10.3390/pathogens12010033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
Cervical cancer (CC) is the most common cancer in women in the lower genital tract. The main risk factor for developing CC is persistent infection with HPV 16. The E6 and E7 oncoproteins of HPV 16 have been related to metabolic reprogramming in cancer through the regulation of the expression and stability of HIF-1α and consequently of the expression of its target genes, such as HIF1A (HIF-1α), SLC2A1 (GLUT1), LDHA, CA9 (CAIX), SLC16A3 (MCT4), and BSG (Basigin or CD147), which are involved in glucose metabolism. This work aimed to evaluate the expression of HIF-1α, GLUT1, LDHA, CAIX, MCT4, and Basigin in patient samples and CC cell lines. To evaluate the expression level of HIF1A, SLC2A1, LDHA, CA9, SLC16A3, and BSG genes in tissue from patients with CC and normal tissue, the TCGA dataset was used. To evaluate the expression level of these genes by RT-qPCR in CC cell lines, HPV-negative (C-33A) and HPV-16-positive (SiHa and Ca Ski) cell lines were used. Increased expression of HIF1A, SLC2A1, LDHA, SLC16A3, and BSG was found in Ca Ski and CA9 in SiHa compared to C-33A. Similar results were observed in CC tissues compared to normal tissue obtained by bioinformatics analysis. In conclusion, the expression of HIF-1α, GLUT1, LDHA, CAIX, MCT4, and BSG genes is increased in CC and HPV-16-positive cell lines.
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Affiliation(s)
- Víctor D. Priego-Hernández
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Adán Arizmendi-Izazaga
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Diana G. Soto-Flores
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Norma Santiago-Ramón
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Milagros D. Feria-Valadez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Hilda Jiménez-Wences
- Laboratorio de Investigación Clínica, Facultad de Ciencias, Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Dinorah N. Martínez-Carrillo
- Laboratorio de Investigación Clínica, Facultad de Ciencias, Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Eric G. Salmerón-Bárcenas
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de Mexico 07360, Mexico
| | - Marco A. Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Luz del C. Alarcón-Romero
- Laboratorio de Investigación en Citopatología e Histoquímica de la Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
- Correspondence: ; Tel.: +52-747-471-0901
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Chae HS, Hong ST. Overview of Cancer Metabolism and Signaling Transduction. Int J Mol Sci 2022; 24:12. [PMID: 36613455 PMCID: PMC9819818 DOI: 10.3390/ijms24010012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
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Affiliation(s)
- Hee-Suk Chae
- Department of Obstetrics and Gynecology, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
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Therapeutic Stimulation of Glycolytic ATP Production for Treating ROS-Mediated Cellular Senescence. Metabolites 2022; 12:metabo12121160. [PMID: 36557198 PMCID: PMC9781421 DOI: 10.3390/metabo12121160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Cellular senescence is conditioned through two interrelated processes, i.e., a reduction in adenosine triphosphate (ATP) and the enhancement of reactive oxygen species (ROS) production levels in mitochondria. ATP shortages primarily influence the energy-intensive synthesis of large biomolecules, such as deoxyribonucleic acid (DNA). In addition, as compared to small biomolecules, large biomolecules are more prone to ROS-mediated damaging effects. Based on the available evidence, we suggest that the stimulation of anaerobic glycolytic ROS-independent ATP production could restrain cellular senescence. Consistent with this notion, non-drug related intermittent hypoxia (IH)-based therapy could be effectively applied in sports medicine, as well as for supporting the physical activity of elderly patients and prophylactics of various age-related disorders. Moreover, drug therapy aiming to achieve the partial blockade of respiratory chain and downstream compensatory glycolysis enhancement could prove to be useful for treating cardiovascular, neurological and hormonal diseases. We maintain that non-drug/drug-related therapeutic interventions applied in combination over the entire lifespan could significantly rejuvenate and prolong a high quality of life for individuals.
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Integrated Tissue and Blood miRNA Expression Profiles Identify Novel Biomarkers for Accurate Non-Invasive Diagnosis of Breast Cancer: Preliminary Results and Future Clinical Implications. Genes (Basel) 2022; 13:genes13111931. [DOI: 10.3390/genes13111931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/10/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
We aimed to identify miRNAs that were closely related to breast cancer (BRCA). By integrating several methods including significance analysis of microarrays, fold change, Pearson’s correlation analysis, t test, and receiver operating characteristic analysis, we developed a decision-tree-based scoring algorithm, called Optimized Scoring Mechanism for Primary Synergy MicroRNAs (O-PSM). Five synergy miRNAs (hsa-miR-139-5p, hsa-miR-331-3p, hsa-miR-342-5p, hsa-miR-486-5p, and hsa-miR-654-3p) were identified using O-PSM, which were used to distinguish normal samples from pathological ones, and showed good results in blood data and in multiple sets of tissue data. These five miRNAs showed accurate categorization efficiency in BRCA typing and staging and had better categorization efficiency than experimentally verified miRNAs. In the Protein-Protein Interaction (PPI) network, the target genes of hsa-miR-342-5p have the most regulatory relationships, which regulate carcinogenesis proliferation and metastasis by regulating Glycosaminoglycan biosynthesis and the Rap1 signaling pathway. Moreover, hsa-miR-342-5p showed potential clinical application in survival analysis. We also used O-PSM to generate an R package uploaded on github (SuFei-lab/OPSM accessed on 22 October 2021). We believe that miRNAs included in O-PSM could have clinical implications for diagnosis, prognostic stratification and treatment of BRCA, proposing potential significant biomarkers that could be utilized to design personalized treatment plans in BRCA patients in the future.
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Cornett K, Puderbaugh A, Back O, Craven R. GAPDH in neuroblastoma: Functions in metabolism and survival. Front Oncol 2022; 12:979683. [PMID: 36267982 PMCID: PMC9577191 DOI: 10.3389/fonc.2022.979683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 09/20/2022] [Indexed: 11/18/2022] Open
Abstract
Neuroblastoma is a pediatric cancer of neural crest cells. It develops most frequently in nerve cells around the adrenal gland, although other locations are possible. Neuroblastomas rely on glycolysis as a source of energy and metabolites, and the enzymes that catalyze glycolysis are potential therapeutic targets for neuroblastoma. Furthermore, glycolysis provides a protective function against DNA damage, and there is evidence that glycolysis inhibitors may improve outcomes from other cancer treatments. This mini-review will focus on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), one of the central enzymes in glycolysis. GAPDH has a key role in metabolism, catalyzing the sixth step in glycolysis and generating NADH. GAPDH also has a surprisingly diverse number of localizations, including the nucleus, where it performs multiple functions, and the plasma membrane. One membrane-associated function of GAPDH is stimulating glucose uptake, consistent with a role for GAPDH in energy and metabolite production. The plasma membrane localization of GAPDH and its role in glucose uptake have been verified in neuroblastoma. Membrane-associated GAPDH also participates in iron uptake, although this has not been tested in neuroblastoma. Finally, GAPDH activates autophagy through a nuclear complex with Sirtuin. This review will discuss these activities and their potential role in cancer metabolism, treatment and drug resistance.
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Kliebhan J, Besse A, Kampa‐Schittenhelm K, Schittenhelm M, Driessen C. Mutant TP53 driving the Warburg Effect in Mantle Cell lymphoma. Clin Case Rep 2022; 10:e6296. [PMID: 36225622 PMCID: PMC9529752 DOI: 10.1002/ccr3.6296] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 08/08/2022] [Accepted: 08/14/2022] [Indexed: 11/10/2022] Open
Abstract
The p53 mutation R273H in tumor cells leads to increased glucose uptake, lactic acidosis, and accelerated tumor growth, as was previously shown in mice. We here present a patient with mantle cell lymphoma harboring this p53_R273H mutation, whose clinical course is characterized by severe lactic acidosis, hypoglycemia, and aggressive disease.
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Affiliation(s)
- Johannes Kliebhan
- Department of Oncology and HematologyCantonal Hospital St GallenSt GallenSwitzerland
| | - Andrej Besse
- Department of Oncology and HematologyCantonal Hospital St GallenSt GallenSwitzerland
| | | | - Marcus Schittenhelm
- Department of Oncology and HematologyCantonal Hospital St GallenSt GallenSwitzerland
| | - Christoph Driessen
- Department of Oncology and HematologyCantonal Hospital St GallenSt GallenSwitzerland
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Hydroxyapatite Biobased Materials for Treatment and Diagnosis of Cancer. Int J Mol Sci 2022; 23:ijms231911352. [PMID: 36232652 PMCID: PMC9569977 DOI: 10.3390/ijms231911352] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/22/2022] Open
Abstract
Great advances in cancer treatment have been undertaken in the last years as a consequence of the development of new antitumoral drugs able to target cancer cells with decreasing side effects and a better understanding of the behavior of neoplastic cells during invasion and metastasis. Specifically, drug delivery systems (DDS) based on the use of hydroxyapatite nanoparticles (HAp NPs) are gaining attention and merit a comprehensive review focused on their potential applications. These are derived from the intrinsic properties of HAp (e.g., biocompatibility and biodegradability), together with the easy functionalization and easy control of porosity, crystallinity and morphology of HAp NPs. The capacity to tailor the properties of DLS based on HAp NPs has well-recognized advantages for the control of both drug loading and release. Furthermore, the functionalization of NPs allows a targeted uptake in tumoral cells while their rapid elimination by the reticuloendothelial system (RES) can be avoided. Advances in HAp NPs involve not only their use as drug nanocarriers but also their employment as nanosystems for magnetic hyperthermia therapy, gene delivery systems, adjuvants for cancer immunotherapy and nanoparticles for cell imaging.
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Guryleva MV, Penzar DD, Chistyakov DV, Mironov AA, Favorov AV, Sergeeva MG. Investigation of the Role of PUFA Metabolism in Breast Cancer Using a Rank-Based Random Forest Algorithm. Cancers (Basel) 2022; 14:cancers14194663. [PMID: 36230586 PMCID: PMC9562210 DOI: 10.3390/cancers14194663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Polyunsaturated fatty acids (PUFAs) and their derivatives, oxylipins, are a constant focus of cancer research due to the relationship between cancer and processes of energy metabolism and inflammation, where a PUFA system is an active player. Only recently have methods been developed that allow for studying such complex systems. Using the Rank-based Random Forest (RF) model, we show that PUFA metabolism genes are critical for the pathogenesis of breast cancer (BC); BC subtypes differ in PUFA metabolism gene expression. The enrichment of BC subtypes with various genes associated with oxylipin signaling pathways indicates a different contribution of these compounds to the biology of subtypes. Abstract Polyunsaturated fatty acid (PUFA) metabolism is currently a focus in cancer research due to PUFAs functioning as structural components of the membrane matrix, as fuel sources for energy production, and as sources of secondary messengers, so called oxylipins, important players of inflammatory processes. Although breast cancer (BC) is the leading cause of cancer death among women worldwide, no systematic study of PUFA metabolism as a system of interrelated processes in this disease has been carried out. Here, we implemented a Boruta-based feature selection algorithm to determine the list of most important PUFA metabolism genes altered in breast cancer tissues compared with in normal tissues. A rank-based Random Forest (RF) model was built on the selected gene list (33 genes) and applied to predict the cancer phenotype to ascertain the PUFA genes involved in cancerogenesis. It showed high-performance of dichotomic classification (balanced accuracy of 0.94, ROC AUC 0.99) We also retrieved a list of the important PUFA genes (46 genes) that differed between molecular subtypes at the level of breast cancer molecular subtypes. The balanced accuracy of the classification model built on the specified genes was 0.82, while the ROC AUC for the sensitivity analysis was 0.85. Specific patterns of PUFA metabolic changes were obtained for each molecular subtype of breast cancer. These results show evidence that (1) PUFA metabolism genes are critical for the pathogenesis of breast cancer; (2) BC subtypes differ in PUFA metabolism genes expression; and (3) the lists of genes selected in the models are enriched with genes involved in the metabolism of signaling lipids.
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Affiliation(s)
- Mariia V. Guryleva
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
| | - Dmitry D. Penzar
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Dmitry V. Chistyakov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- Correspondence: ; Tel.: +7-495-939-4332
| | - Andrey A. Mironov
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
- Kharkevich Institute of Information Transmission Problems, Russian Academy of Sciences, 127051 Moscow, Russia
| | - Alexander V. Favorov
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 119991 Moscow, Russia
- School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Marina G. Sergeeva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
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Uen W, Tseng T, Wu CP, Lee S. Detachment stress mediated bioenergetic switch of malignant melanoma cells into anti-Warburg phenotype. Aging (Albany NY) 2022; 14:5511-5522. [PMID: 35802540 PMCID: PMC9320547 DOI: 10.18632/aging.204164] [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: 04/05/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022]
Abstract
One of the biological features of cancer cells is their aerobic glycolysis by extensive glucose fermentation to harvest energy, so called Warburg effect. Melanoma is one of the most aggressive human cancers with poor prognosis and high mortality for its high metastatic ability. During the metastatic process, the metastatic tumor cells should survive under detachment stress. However, whether the detachment stress could affect the tumor phenotype is worthy to investigate. We had established the cell model of human melanoma cells under detachment stress, which mimicked circulating melanoma. It had been demonstrated that the detachment stress altered melanoma cell activities, malignancy, and drug sensitivity. In this study, we found that adherent melanoma cells were more sensitive to glucose depletion. Gene expression profiling altered expressions of transporters associated with glucose metabolism. In addition, detachment stress reduced lactate secretion owing to the reduced MCT4 and GLUT1 expressions, the altered glycolytic and respiratory capacities, and the increased superoxide production. Detachment stress also increases the sensitivity of melanoma cells toward the blockade of electron transport chains. Investigation of the change in glucose metabolism of melanoma cells under detachment stress would be critical to provide a novel molecular mechanism to develop potential therapeutics.
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Affiliation(s)
- WuChing Uen
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan.,Department of Hematology and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Shih-Lin, Taipei City, Taiwan
| | - TingTing Tseng
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
| | - Ching-Po Wu
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
| | - ShaoChen Lee
- School of Medicine, Fu Jen Catholic University, Xinzhuang, New Taipei City, Taiwan
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Reyna-Hernández MA, Alarcón-Romero LDC, Ortiz-Ortiz J, Illades-Aguiar B, Jiménez-López MA, Ocampo-Bárcenas A, Morrugares-Ixtepan MO, Torres-Rojas FI. GLUT1, LDHA, and MCT4 Expression Is Deregulated in Cervical Cancer and Precursor Lesions. J Histochem Cytochem 2022; 70:437-446. [PMID: 35615882 PMCID: PMC9169107 DOI: 10.1369/00221554221101662] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022] Open
Abstract
Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I (n=20), CIN II/III (n=16), or ICC (n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.
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Affiliation(s)
- Ma. A. Reyna-Hernández
- Laboratorio de Citopatología e Histoquímica,
Instituto Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de
Juárez, México
| | - Luz del C. Alarcón-Romero
- Laboratorio de Citopatología e Histoquímica,
Instituto Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de
Juárez, México
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Marco A. Jiménez-López
- Facultad de Ciencias Químico-Biológicas,
Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, México, and
Anatomía Patológica, Instituto Estatal de Cancerología “Dr. Arturo Beltrán
Ortega,” Acapulco de Juárez, México
| | - Azucena Ocampo-Bárcenas
- Laboratorio de Patología Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
| | - Martin O. Morrugares-Ixtepan
- Facultad de Ciencias Químico-Biológicas,
Universidad Autónoma de Guerrero, Chilpancingo de los Bravo, México, and
Anatomía Patológica, Instituto Estatal de Cancerología “Dr. Arturo Beltrán
Ortega,” Acapulco de Juárez, México
| | - Francisco I. Torres-Rojas
- Laboratorio de Biomedicina Molecular, Instituto
Estatal de Cancerología “Dr. Arturo Beltrán Ortega,” Acapulco de Juárez,
México
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Resurreccion EP, Fong KW. The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer. Metabolites 2022; 12:metabo12060488. [PMID: 35736421 PMCID: PMC9230859 DOI: 10.3390/metabo12060488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/06/2023] Open
Abstract
Our understanding of prostate cancer (PCa) has shifted from solely caused by a few genetic aberrations to a combination of complex biochemical dysregulations with the prostate metabolome at its core. The role of metabolomics in analyzing the pathophysiology of PCa is indispensable. However, to fully elucidate real-time complex dysregulation in prostate cells, an integrated approach based on metabolomics and other omics is warranted. Individually, genomics, transcriptomics, and proteomics are robust, but they are not enough to achieve a holistic view of PCa tumorigenesis. This review is the first of its kind to focus solely on the integration of metabolomics with multi-omic platforms in PCa research, including a detailed emphasis on the metabolomic profile of PCa. The authors intend to provide researchers in the field with a comprehensive knowledge base in PCa metabolomics and offer perspectives on overcoming limitations of the tool to guide future point-of-care applications.
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Affiliation(s)
- Eleazer P. Resurreccion
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA;
| | - Ka-wing Fong
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA;
- Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA
- Correspondence: ; Tel.: +1-859-562-3455
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Ijurko C, González‐García N, Galindo‐Villardón P, Hernández‐Hernández Á. A 29-gene signature associated with NOX2 discriminates acute myeloid leukemia prognosis and survival. Am J Hematol 2022; 97:448-457. [PMID: 35073432 PMCID: PMC9303675 DOI: 10.1002/ajh.26477] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 12/19/2022]
Abstract
The molecular complexity displayed in acute myeloid leukemia (AML) hinders patient stratification and treatment decisions. Previous studies support the utility of using specific gene panels for this purpose. Focusing on two salient features of AML, the production of reactive oxygen species (ROS) by NADPH oxidases (NOX) and metabolism, we aimed to identify a gene panel that could improve patient stratification. A pairwise comparison of AML versus healthy gene expression revealed the downregulation of four members of the NOX2 complex including CYBB (coding for NOX2) in AML patients. We analyzed the expression of 941 genes related to metabolism and found 28 genes with expression correlated to CYBB. This panel of 29 genes (29G) effectively divides AML samples according to their prognostic group. The robustness of 29G was confirmed by 6 AML cohort datasets with a total of 1821 patients (overall accuracies of 85%, 78%, 80%, 75%, 59% and 83%). An expression index (EI) was developed according to the expression of the selected discriminatory genes. Overall Survival (OS) was higher for low 29G expression index patients than for the high 29G expression index group, which was confirmed in three different datasets with a total of 1069 patients. Moreover, 29G can dissect intermediate‐prognosis patients in four clusters with different OS, which could improve the current AML stratification scheme. In summary, we have found a gene signature (29G) that can be used for AML classification and for OS prediction. Our results confirm NOX and metabolism as suitable therapeutic targets in AML.
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Affiliation(s)
- Carla Ijurko
- Departamento de Bioquímica y Biología Molecular Universidad de Salamanca Salamanca Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain
| | - Nerea González‐García
- Instituto de Investigación Biomédica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain
- Departamento de Estadística Universidad de Salamanca Salamanca Spain
| | - Purificación Galindo‐Villardón
- Instituto de Investigación Biomédica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain
- Departamento de Estadística Universidad de Salamanca Salamanca Spain
- Centro de Investigación Institucional (CII) Universidad Bernardo O'Higgins Santiago Chile
- Centro de Gestión de Estudios Estadísticos Universidad Estatal de Milagro Milagro Guayas Ecuador
| | - Ángel Hernández‐Hernández
- Departamento de Bioquímica y Biología Molecular Universidad de Salamanca Salamanca Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL) Hospital Universitario de Salamanca Salamanca Spain
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36
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Afzaal A, Rehman K, Kamal S, Akash MSH. Versatile role of sirtuins in metabolic disorders: From modulation of mitochondrial function to therapeutic interventions. J Biochem Mol Toxicol 2022; 36:e23047. [PMID: 35297126 DOI: 10.1002/jbt.23047] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 01/11/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022]
Abstract
Sirtuins (SIRT1-7) are distinct histone deacetylases (HDACs) whose activity is determined by cellular metabolic status andnicotinamide adenine dinucleotide (NAD+ ) levels. HDACs of class III are the members of the SIRT's protein family. SIRTs are the enzymes that modulate mitochondrial activity and energy metabolism. SIRTs have been linked to a number of clinical and physiological operations, such as energy responses to low-calorie availability, aging, stress resistance, inflammation, and apoptosis. Mammalian SIRT2 orthologs have been identified as SIRT1-7 that are found in several subcellular sections, including the cytoplasm (SIRT1, 2), mitochondrial matrix (SIRT3, 4, 5), and the core (SIRT1, 2, 6, 7). For their deacetylase or ADP-ribosyl transferase action, all SIRTs require NAD+ and are linked to cellular energy levels. Evolutionarily, SIRT1 is related to yeast's SIRT2 as well as received primary attention in the circulatory system. An endogenous protein, SIRT1 is involved in the development of heart failure and plays a key role in cell death and survival. SIRT2 downregulation protects against ischemic-reperfusion damage. Increase in human longevity is caused by an increase in SIRT3 expression. Cardiomyocytes are also protected by SIRT3 from oxidative damage and aging, as well as suppressing cardiac hypertrophy. SIRT4 and SIRT5 perform their roles in the heart. SIRT6 has also been linked to a reduction in heart hypertrophy. SIRT7 is known to be involved in the regulation of stress responses and apoptosis in the heart.
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Affiliation(s)
- Ammara Afzaal
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
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Masui K, Cavenee WK, Mischel PS, Shibata N. The metabolomic landscape plays a critical role in glioma oncogenesis. Cancer Sci 2022; 113:1555-1563. [PMID: 35271755 PMCID: PMC9128185 DOI: 10.1111/cas.15325] [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: 01/07/2022] [Revised: 02/24/2022] [Accepted: 03/04/2022] [Indexed: 12/01/2022] Open
Abstract
Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate‐limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular‐genetic advances have revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio‐temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omics approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an omics perspective and with a particular focus on the genomically well characterized malignant brain tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.
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Affiliation(s)
- Kenta Masui
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
| | - Webster K Cavenee
- Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, 92093, USA
| | - Paul S Mischel
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.,ChEM-H, Stanford University, Stanford, CA, 94305, USA
| | - Noriyuki Shibata
- Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan
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38
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Gyamfi J, Kim J, Choi J. Cancer as a Metabolic Disorder. Int J Mol Sci 2022; 23:ijms23031155. [PMID: 35163079 PMCID: PMC8835572 DOI: 10.3390/ijms23031155] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.
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Affiliation(s)
- Jones Gyamfi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Jinyoung Kim
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
| | - Junjeong Choi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Correspondence: ; Tel.: +82-32-749-4521; Fax: +82-32-749-4105
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Mu J, Tian Y, Liu F, Wang Z, Tan R, Zhang B, Quan P, Zhang H, Yang J, Yuan P. Mitochondrial transcription factor B1 promotes the progression of hepatocellular carcinoma via enhancing aerobic glycolysis. J Cell Commun Signal 2021; 16:223-238. [PMID: 34825289 DOI: 10.1007/s12079-021-00658-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/09/2021] [Indexed: 12/27/2022] Open
Abstract
Mitochondrial dysfunctions play crucial roles in the carcinogenesis of various human cancers. However, the molecular mechanisms leading to mitochondrial dysfunction and thus cancer progression remains largely unclear. TFB1M (mitochondrial transcription factor B1) is a mitochondrial DNA-binding protein that activates the transcription of mitochondrial DNA. Our bioinformatics analysis indicated a significant up-regulation of TFB1M in hepatocellular carcinoma (HCC). Here, we investigated its clinical significance and biological functions in this malignancy. Here, we found that TFB1M was significantly upregulated in HCC cells probably due to decreased miR-130a-3p expression. High TFB1M expression was positively associated with poor patient survival in HCC. TFB1M contributes to HCC growth and metastasis by promoting cell cycle progression, epithelia-mesenchymal transition (EMT), and inhibiting cell apoptosis. Mechanistically, the metabolic switch from oxidative phosphorylation to glycolysis contributed to the promotion of tumor growth and metastasis by TFB1M overexpression in HCC cells. In summary, we demonstrate that TFB1M plays a crucial oncogenic role in HCC progression, indicating TFB1M as a promising prognostic marker and therapeutic target in HCC.
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Affiliation(s)
- Jiao Mu
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China.,Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.,Department of Hematology, Xi'an Central Hospital, Xi'an, 710003, Shaanxi, China
| | - Yiyuan Tian
- Physiology Divion of Yan'an University Medical College, Yan'an, 716000, Shaanxi, China
| | - Fengzhou Liu
- Aerospace Clinical Medical Center, School of Aerospace Medicine, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Zijun Wang
- Battalion of the First Regiment of Cadets of Basic Medicine, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Rui Tan
- Department of Orthopaedics, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Bei Zhang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China
| | - Penghe Quan
- Department of Urology, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Hongxin Zhang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China.
| | - Jingyue Yang
- Department of Oncology, Xijing Hospital, Air Force Military Medical University, 169 Changle West Road, Xi'an, 710032, Shaanxi, China.
| | - Peng Yuan
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Xi'an, 710038, Shaanxi, China. .,State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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Steroid receptor RNA activator gene footprint in the progression and drug resistance of colorectal cancer through oxidative phosphorylation pathway. Life Sci 2021; 285:119950. [PMID: 34520769 DOI: 10.1016/j.lfs.2021.119950] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND The steroid receptor RNA activator 1 (SRA1) gene is involved in the progression of various cancers via different molecular mechanisms mediated by long non-coding RNA SRA (lncRNA SRA). This study aimed to evaluate the lncRNA SRA effect on the tumor progression of colorectal cancer (CRC). METHODS SRA1 expression was assessed in the cancer genome atlas datasets, CRC cell lines, and tumor specimens. Meta-analysis and gene co-expression network analysis were performed to identify pathways related to SRA1. RNA interference and cell treatment were utilized to examine the role of SRA1 expression in HT-29 and Caco-2 cell lines. Also, the effect of SRA1 expression was investigated on drug resistance, clinical parameters, and mutations in CRC samples. RESULTS The SRA1 transcripts, especially lncRNA SRA, were dysregulated in CRC tissue samples compared with normal tissue samples. Furthermore, SRA1 depletion decreased colony formation and proliferation while induced apoptosis in HT-29 and Caco-2 cells. In silico analyses indicated that SRA1 level was correlated with expression levels of oxidative phosphorylation (OXPHOS) genes. LncRNA SRA expression increased in response to the increased oxidative capacity, and when lncRNA SRA was knocked down, the expression level of OXPHOS pathway genes, including NDUFB5 and ATP5F1B, was changed. Also, KRAS-mutant samples had the highest SRA1 expression level. CONCLUSIONS LncRNA SRA could function as an oncogene through the OXPHOS pathway in CRC, and serve as a potential biomarker for identifying CRC subtype with KRAS mutations. The findings suggest that lncRNA SRA might be a therapeutic target to inhibit cell proliferation in CRC.
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Wang T, Lyu CY, Jiang YH, Dong XY, Wang Y, Li ZH, Wang JX, Xu RR. A drug-biomarker interaction model to predict the key targets of Scutellaria barbata D. Don in adverse-risk acute myeloid leukaemia. Mol Divers 2021; 25:2351-2365. [PMID: 32676746 DOI: 10.1007/s11030-020-10124-z] [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] [Received: 05/08/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023]
Abstract
A poor prognosis, relapse and resistance are burning issues during adverse-risk acute myeloid leukaemia (AML) treatment. As a natural medicine, Scutellaria barbata D. Don (SBD) has shown impressive antitumour activity in various cancers. Thus, SBD may become a potential drug in adverse-risk AML treatment. This study aimed to screen the key targets of SBD in adverse-risk AML using the drug-biomarker interaction model through bioinformatics and network pharmacology methods. First, the adverse-risk AML-related critical biomarkers and targets of SBD active ingredient were obtained from The Cancer Genome Atlas database and several pharmacophore matching databases. Next, the protein-protein interaction network was constructed, and topological analysis and pathway enrichment were used to screen key targets and main pathways of intervention of SBD in adverse-risk AML. Finally, molecular docking was implemented for key target verification. The results suggest that luteolin and quercetin are the main active components of SBD against adverse-risk AML, and affected drug resistance, apoptosis, immune regulation and angiogenesis through the core targets AKT1, MAPK1, IL6, EGFR, SRC, VEGFA and TP53. We hope the proposed drug-biomarker interaction model provides an effective strategy for the research and development of antitumour drugs.
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Affiliation(s)
- Teng Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Chun-Yi Lyu
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Yue-Hua Jiang
- Central Laboratory of Affiliated Hospital of Shandong, University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Xue-Yan Dong
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Yan Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Zong-Hong Li
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Jin-Xin Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China
| | - Rui-Rong Xu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong Province, People's Republic of China.
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Footprints of microRNAs in Cancer Biology. Biomedicines 2021; 9:biomedicines9101494. [PMID: 34680611 PMCID: PMC8533183 DOI: 10.3390/biomedicines9101494] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/19/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional gene regulation. Over the past years, various studies have demonstrated the role of aberrant miRNA expression in the onset of cancer. The mechanisms by which miRNA exerts its cancer-promoting or inhibitory effects are apparent through the various cancer hallmarks, which include selective proliferative advantage, altered stress response, vascularization, invasion and metastasis, metabolic rewiring, the tumor microenvironment and immune modulation; therefore, this review aims to highlight the association between miRNAs and the various cancer hallmarks by dissecting the mechanisms of miRNA regulation in each hallmark separately. It is hoped that the information presented herein will provide further insights regarding the role of cancer and serve as a guideline to evaluate the potential of microRNAs to be utilized as biomarkers and therapeutic targets on a larger scale in cancer research.
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Regulatory role and mechanism of m 6A RNA modification in human metabolic diseases. MOLECULAR THERAPY-ONCOLYTICS 2021; 22:52-63. [PMID: 34485686 PMCID: PMC8399361 DOI: 10.1016/j.omto.2021.05.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Metabolic diseases caused by disorders in amino acids, glucose, lipid metabolism, and other metabolic risk factors show high incidences in young people, and current treatments are ineffective. N6-methyladenosine (m6A) RNA modification is a post-transcriptional regulation of gene expression with several effects on physiological processes and biological functions. Recent studies report that m6A RNA modification is involved in various metabolic pathways and development of common metabolic diseases, making it a potential disease-specific therapeutic target. This review explores components, mechanisms, and research methods of m6A RNA modification. In addition, we summarize the progress of research on m6A RNA modification in metabolism-related human diseases, including diabetes, obesity, non-alcoholic fatty liver disease, osteoporosis, and cancer. Furthermore, opportunities and the challenges facing basic research and clinical application of m6A RNA modification in metabolism-related human diseases are discussed. This review is meant to enhance our understanding of the molecular mechanisms, research methods, and clinical significance of m6A RNA modification in metabolism-related human diseases.
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Miranda-Gonçalves V, Gonçalves CS, Granja S, Vieira de Castro J, Reis RM, Costa BM, Baltazar F. MCT1 Is a New Prognostic Biomarker and Its Therapeutic Inhibition Boosts Response to Temozolomide in Human Glioblastoma. Cancers (Basel) 2021; 13:cancers13143468. [PMID: 34298681 PMCID: PMC8306807 DOI: 10.3390/cancers13143468] [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: 05/18/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Glioblastoma, the brain tumour with highest prevalence and lethality, exhibits a characteristic glycolytic phenotype with increased lactate production. Recently, we reported a MCT1 overexpression in GBMs tumours, being associated to tumour growth and aggressiveness. Thus, we aimed to disclose the role of MCT1 in GBM prognosis and in vivo therapy response. Importantly, MCT1 overexpression is associated with poor prognosis of GBM. Moreover, MCT1 inhibition retards GBM tumour growth and boosts response to temozolomide treatment. Abstract Background: Glioblastomas (GBMs) present remarkable metabolism reprograming, in which many cells display the “Warburg effect”, with the production of high levels of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). We described previously that MCT1 is up-regulated in human GBM samples, and MCT1 inhibition decreases glioma cell viability and aggressiveness. In the present study, we aimed to unveil the role of MCT1 in GBM prognosis and to explore it as a target for GBM therapy in vivo. Methods: MCT1 activity and protein expression were inhibited by AR-C155858 and CHC compounds or stable knockdown with shRNA, respectively, to assess in vitro and in vivo the effects of MCT1 inhibition and on response of GBM to temozolomide. Survival analyses on GBM patient cohorts were performed using Cox regression and Log-rank tests. Results: High levels of MCT1 expression were revealed to be a predictor of poor prognosis in multiple cohorts of GBM patients. Functionally, in U251 GBM cells, MCT1 stable knockdown decreased glucose consumption and lactate efflux, compromising the response to the MCT1 inhibitors CHC and AR-C155858. MCT1 knockdown significantly increased the survival of orthotopic GBM intracranial mice models when compared to their control counterparts. Furthermore, MCT1 downregulation increased the sensitivity to temozolomide in vitro and in vivo, resulting in significantly longer mice survival. Conclusions: This work provides first evidence for MCT1 as a new prognostic biomarker of GBM survival and further supports MCT1 targeting, alone or in combination with classical chemotherapy, for the treatment of GBM.
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Affiliation(s)
- Vera Miranda-Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Céline S. Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Sara Granja
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Research Centre in Health and Environment (CISA), School of Health (ESS), Polytechnic Institute of Porto (P.PORTO), 4200-072 Porto, Portugal
- Department of Pathological, Cytological and Thanatological Anatomy, School of Health (ESS), Polytechnic Institute of Porto (P.PORTO), 4200-072 Porto, Portugal
| | - Joana Vieira de Castro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Rui M. Reis
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil
| | - Bruno M. Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; (V.M.-G.); (C.S.G.); (S.G.); (J.V.d.C.); (R.M.R.); (B.M.C.)
- ICVS/3Bs-PT Government Associate Laboratory, 4805-017 Guimarães, Portugal
- Correspondence: ; Tel.: +351-253-604828
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Zhang H, Li Z, Wang Y, Kong Y. O-GlcNAcylation is a key regulator of multiple cellular metabolic pathways. PeerJ 2021. [DOI: 10.7717/peerj.11443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
O-GlcNAcylation modifies proteins in serine or threonine residues in the nucleus, cytoplasm, and mitochondria. It regulates a variety of cellular biological processes and abnormal O-GlcNAcylation is associated with diabetes, cancer, cardiovascular disease, and neurodegenerative diseases. Recent evidence has suggested that O-GlcNAcylation acts as a nutrient sensor and signal integrator to regulate metabolic signaling, and that dysregulation of its metabolism may be an important indicator of pathogenesis in disease. Here, we review the literature focusing on O-GlcNAcylation regulation in major metabolic processes, such as glucose metabolism, mitochondrial oxidation, lipid metabolism, and amino acid metabolism. We discuss its role in physiological processes, such as cellular nutrient sensing and homeostasis maintenance. O-GlcNAcylation acts as a key regulator in multiple metabolic processes and pathways. Our review will provide a better understanding of how O-GlcNAcylation coordinates metabolism and integrates molecular networks.
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Costa Dos Santos G, Renovato-Martins M, de Brito NM. The remodel of the "central dogma": a metabolomics interaction perspective. Metabolomics 2021; 17:48. [PMID: 33969452 PMCID: PMC8106972 DOI: 10.1007/s11306-021-01800-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/30/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the "central dogma." Subsequently, the relationships between different steps of the "central dogma" have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the "central dogma"; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. AIM OF REVIEW Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. KEY SCIENTIFIC CONCEPTS OF REVIEW Metabolites are the beginning and the end of the flux of information.
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Affiliation(s)
- Gilson Costa Dos Santos
- Laboratory of NMR Metabolomics, IBRAG, Department of Genetics, State University of Rio de Janeiro, Rio de Janeiro, 20551-030, Brazil.
| | - Mariana Renovato-Martins
- Department of Cellular and Molecular Biology, IB, Federal Fluminense University, Niterói, 24210-200, Brazil
| | - Natália Mesquita de Brito
- Laboratory of Cellular and Molecular Pharmacology, IBRAG, Department of Cell Biology, State University of Rio de Janeiro, Rio de Janeiro, 20551-030, Brazil.
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Zhang S, Wang X, Zhang R, Cui Y, Zhang H, Song W, Hou X, Fu S, Gao Q, Liu S. A GLUT1 inhibitor-based fluorogenic probe for Warburg effect-targeted drug screening and diagnostic imaging of hyperglycolytic cancers. Anal Chim Acta 2021; 1167:338593. [PMID: 34049629 DOI: 10.1016/j.aca.2021.338593] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/16/2021] [Accepted: 04/27/2021] [Indexed: 11/28/2022]
Abstract
Increased expression of glucose transporters, especially GLUT1 has been proven to be involved in the Warburg effect. Therefore, GLUT1-targeted oncological approaches are being successfully employed for clinical tumor diagnostic imaging (e.g. the 18F-FDG/PET), drug delivery and novel anticancer drug development. Despite the long history of the Warburg effect-targeted cancer diagnosis, other than antibody labeling, there have been no imaging tools developed for direct detection of the GLUT1 expression. Herein, we report the new strategy of using a non-antibody GLUT1 binding probe for Warburg effect-based tumor detection and diagnostic imaging. By specifically inhibits the transport function of GLUT1, the newly designed fluorescent probe, CUM-5, was found to be a useful tool not only for sensitive GLUT1-mediated cancer cell detection, but also for cell-based high-throughput GLUT inhibitor screening. In in vivo studies, CUM-5 shows clear advantages including desirable tumor-to-normal tissue contrast and excellent tumor selectivity (Tm/Bkg and Tm/Torg), as well as high fluorescence stability (long response time) and ideal physiological biocompatibility. In particular, the GLUT1 inhibitor probe offers the potential use for glycolysis-based diagnostic imaging in triple-negative breast cancer which is claimed to have unsatisfactory results with FDG/PET diagnosis, thus remaining a highly metastatic and lethal disease with a need for sensitive and precise identification.
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Affiliation(s)
- Shunjie Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Xinyu Wang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Ru Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Yujun Cui
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Transplantation Center, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, 300192, PR China
| | - Heming Zhang
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanhe Road, Shijiazhuang, Hebei, 050035, PR China
| | - Weijie Song
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, West Huanhu Road, Hexi District, Tianjin, 300060, PR China
| | - Xiaohan Hou
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China
| | - Shibo Fu
- Department of Biology, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin, 300384, PR China
| | - Qingzhi Gao
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China.
| | - Shengnan Liu
- Institute of Molecular Plus, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, PR China.
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Ruan GJ, Gandhi S, Abeykoon JP, Schram S, Habermann TM, Sandefur BJ, Witzig TE. Elevated Serum Lactate in Patients With Lymphoma: It Is Not Always Infection. Mayo Clin Proc Innov Qual Outcomes 2021; 5:423-430. [PMID: 33997638 PMCID: PMC8105511 DOI: 10.1016/j.mayocpiqo.2021.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2023] Open
Abstract
OBJECTIVE To distinguish between sepsis only vs progressive lymphoma in patients with a history of lymphoma who present to the hospital with lactic acidosis. PATIENTS AND METHODS We identified patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma from January 2014 to December 2015. Patients were categorized into 2 groups: sepsis only or progressive lymphoma. Two-sided Wilcoxon rank sum test and χ1/Fisher exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier analysis was used to estimate overall survival (OS). RESULTS A total of 51 patients were identified; 33 (65%) patients were categorized into the sepsis only group, and 18 (35%), into the progressive lymphoma group. Values for serum lactate dehydrogenase (LDH) drawn during hospitalization were statistically different between the sepsis only and progressive lymphoma groups (median, 262 vs 665 U/L; P=.005), respectively. The sensitivity and specificity of serum LDH level 2 or more times the upper limit of normal for progressive lymphoma were 56% (95% CI, 33% to 79%) and 85% (95% CI, 73% to 97%), respectively. Serum LDH level was independently predictive of inferior OS (hazard ratio, 27.8; 95% CI, 4.0 to 160.1; P<.001), while serum albumin level (hazard ratio, 0.05; 95% CI, 0.01 to 0.27; P<.001) was independently predictive of improved OS. CONCLUSION Serum LDH levels used in conjunction with serial serum lactate values may be reliable markers to differentiate patients with progressive lymphomatous disease from patients with lymphoma with sepsis only. The LDH levels should be obtained in all patients with lymphoma who present to the hospital with lactic acidosis.
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Key Words
- ATP, adenosine triphosphate
- CT, computed tomography
- CoA, coenzyme A
- DLBCL, diffuse large B-cell lymphoma
- GLUT, facilitative glucose transporter
- HR, hazard ratio
- IQR, interquartile range
- LDH, lactate dehydrogenase
- MCT, monocarboxylate transporter
- NAD, nicotinamide adenine dinucleotide
- NADH, nicotinamide adenine dinucleotide and hydrogen
- NHL, non-Hodgkin lymphoma
- O2, oxygen
- OS, overall survival
- TCA, tricarboxylic acid
- ULN, upper limit of normal
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Affiliation(s)
- Gordon J. Ruan
- Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | | | | | - Susan Schram
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | - Thomas E. Witzig
- Division of Hematology, Mayo Clinic, Rochester, MN
- Correspondence: Address to Thomas E. Witzig, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Li M, Wu C, Yang Y, Zheng M, Yu S, Wang J, Chen L, Li H. 3-Phosphoglycerate dehydrogenase: a potential target for cancer treatment. Cell Oncol (Dordr) 2021; 44:541-556. [PMID: 33735398 DOI: 10.1007/s13402-021-00599-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Metabolic changes have been recognized as an important hallmark of cancer cells. Cancer cells can promote their own growth and proliferation through metabolic reprogramming. Particularly, serine metabolism has frequently been reported to be dysregulated in tumor cells. 3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the serine biosynthesis pathway and acts as a rate-limiting enzyme involved in metabolic reprogramming. PHGDH upregulation has been observed in many tumor types, and inhibition of PHGDH expression has been reported to inhibit the proliferation of PHGDH-overexpressing tumor cells, indicating that it may be utilized as a target for cancer treatment. Recently identified inhibitors targeting PHGDH have already shown effectiveness. A further in-depth analysis and concomitant development of PHGDH inhibitors will be of great value for the treatment of cancer. CONCLUSIONS In this review we describe in detail the role of PHGDH in various cancers and inhibitors that have recently been identified to highlight progression in cancer treatment. We also discuss the development of new drugs and treatment modalities based on PHGDH targets. Overexpression of PHGDH has been observed in melanoma, breast cancer, nasopharyngeal carcinoma, parathyroid adenoma, glioma, cervical cancer and others. PHGDH may serve as a molecular biomarker for the diagnosis, prognosis and treatment of these cancers. The design and development of novel PHGDH inhibitors may have broad implications for cancer treatment. Therapeutic strategies of PHGDH inhibitors in combination with traditional chemotherapeutic drugs may provide new perspectives for precision medicine and effective personalized treatment for cancer patients.
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Affiliation(s)
- Mingxue Li
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Canrong Wu
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Yueying Yang
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Silin Yu
- Department of Medicinal Chemistry and Natural Medicine Chemistry (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, 150081, China
| | - Jinhui Wang
- Department of Medicinal Chemistry and Natural Medicine Chemistry (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, 150081, China.
| | - Lixia Chen
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, School of Pharmacy, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. .,Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
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50
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Arizmendi-Izazaga A, Navarro-Tito N, Jiménez-Wences H, Mendoza-Catalán MA, Martínez-Carrillo DN, Zacapala-Gómez AE, Olea-Flores M, Dircio-Maldonado R, Torres-Rojas FI, Soto-Flores DG, Illades-Aguiar B, Ortiz-Ortiz J. Metabolic Reprogramming in Cancer: Role of HPV 16 Variants. Pathogens 2021; 10:pathogens10030347. [PMID: 33809480 PMCID: PMC7999907 DOI: 10.3390/pathogens10030347] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/13/2021] [Accepted: 03/14/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic reprogramming is considered one of the hallmarks in cancer and is characterized by increased glycolysis and lactate production, even in the presence of oxygen, which leads the cancer cells to a process called “aerobic glycolysis” or “Warburg effect”. The E6 and E7 oncoproteins of human papillomavirus 16 (HPV 16) favor the Warburg effect through their interaction with a molecule that regulates cellular metabolism, such as p53, retinoblastoma protein (pRb), c-Myc, and hypoxia inducible factor 1α (HIF-1α). Besides, the impact of the E6 and E7 variants of HPV 16 on metabolic reprogramming through proteins such as HIF-1α may be related to their oncogenicity by favoring cellular metabolism modifications to satisfy the energy demands necessary for viral persistence and cancer development. This review will discuss the role of HPV 16 E6 and E7 variants in metabolic reprogramming and their contribution to developing and preserving the malignant phenotype of cancers associated with HPV 16 infection.
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Affiliation(s)
- Adán Arizmendi-Izazaga
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (N.N.-T.); (M.O.-F.)
| | - Hilda Jiménez-Wences
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (H.J.-W.); (D.N.M.-C.)
- Laboratorio de Investigación Clínica, Facultad de Ciencias, Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
| | - Miguel A. Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (H.J.-W.); (D.N.M.-C.)
| | - Dinorah N. Martínez-Carrillo
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (H.J.-W.); (D.N.M.-C.)
- Laboratorio de Investigación Clínica, Facultad de Ciencias, Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
| | - Ana E. Zacapala-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
| | - Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (N.N.-T.); (M.O.-F.)
| | - Roberto Dircio-Maldonado
- Laboratorio de Investigación Clínica, Facultad de Ciencias, Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico;
- Laboratorio de Diagnóstico e Investigación en Salud, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Francisco I. Torres-Rojas
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
| | - Diana G. Soto-Flores
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
- Laboratorio de Diagnóstico e Investigación en Salud, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (A.A.-I.); (M.A.M.-C.); (A.E.Z.-G.); (F.I.T.-R.); (D.G.S.-F.); (B.I.-A.)
- Laboratorio de Investigación en Biomoléculas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia La Haciendita, Chilpancingo C.P. 39090, Guerrero, Mexico; (H.J.-W.); (D.N.M.-C.)
- Correspondence: ; Tel.: +52-747-471-0901
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