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Indongo G, Varghese S, Shkhair AI, Abraham MK, Rajeevan G, Kala AB, Madanan AS, George S. Fe(III)-quenched cysteine-capped copper nanoclusters as a selective fluorescence turn-on sensor for valine: A potential cancer biomarker candidate. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 335:125981. [PMID: 40054147 DOI: 10.1016/j.saa.2025.125981] [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: 01/05/2025] [Revised: 02/21/2025] [Accepted: 03/01/2025] [Indexed: 03/24/2025]
Abstract
This study introduces a fluorescence turn-on sensor for the selective detection of valine, an amino acid increasingly recognized as a potential biomarker in cancer diagnostics, using iron(III) (Fe3+) quenched L-cysteine capped copper nanoclusters (L-cys@CuNCs) based on the paramagnetic quenching mechanism of Fe3+. The L-cys@CuNCs, synthesized through a one-pot hydrothermal method, exhibit stable green fluorescence, high photostability and a detection limit of 3.00 µM for valine. Restoration of fluorescence upon interaction with valine enables a highly sensitive detection, with strong selectivity against other amino acids and ions. This specificity makes the sensor particularly promising for screening valine in biological samples, supporting its potential as a non-invasive cancer biomarker. To enhance practicality, a paper-based assay was developed, demonstrating its adaptability to point of care formats. Additionally, testing in human saliva and urine samples validated the probe's utility in real biological conditions, underscoring its potential in non-invasive cancer diagnostics. This biosensing platform offers a rapid, accessible tool for valine detection, contributing to early cancer detection and patient screening in clinical and resource limited settings.
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Affiliation(s)
- Geneva Indongo
- Department of Biotechnology, Faculty of Applied Sciences and Technology, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Susan Varghese
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Ali Ibrahim Shkhair
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Merin K Abraham
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Greeshma Rajeevan
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Arathy B Kala
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Anju S Madanan
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India
| | - Sony George
- Department of Chemistry, School of Physical and Mathematical Sciences, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India; International Inter University Centre for Sensing and Imaging (IIUCSI), Department of Chemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram 695581, Kerala, India.
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Cai R, Ke L, Zhao Y, Zhao J, Zhang H, Zheng P, Xin L, Ma C, Lin Y. NMR-based metabolomics combined with metabolic pathway analysis reveals metabolic heterogeneity of colorectal cancer tissue at different anatomical locations and stages. Int J Cancer 2025; 156:1644-1655. [PMID: 39629979 PMCID: PMC11826128 DOI: 10.1002/ijc.35273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 02/16/2025]
Abstract
Colorectal cancer (CRC) still remains the leading cause of cancer death worldwide. This study aimed to profile the metabolic differences of colorectal cancer tissues (CCT) at different stages and sites, as compared with their distant noncancerous tissues (DNT), to investigate the temporal and spatial heterogeneities of metabolic characterization. Our NMR-based metabolomics fingerprinting revealed that many of the metabolite levels were significantly altered in CCT compared to DNT and esophageal cancer tissues, indicating deregulations of glucose metabolism, one-carbon metabolism, glutamine metabolism, amino acid metabolism, fatty acid metabolism, TCA cycle, choline metabolism, and so forth. A total of five biomarker metabolites, including glucose, glutamate, alanine, valine and histidine, were identified to distinguish between early and advanced stages of CCT. Metabolites that distinguish the different anatomical sites of CCT include glucose, glycerol, glutamine, inositol, succinate, and citrate. Those significant metabolic differences in CRC tissues at different pathological stages and sites suggested temporal and spatial heterogeneities of metabolic characterization in CCT, providing a metabolic foundation for further study on biofluid metabolism in CRC early detection.
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Affiliation(s)
- Rongzhi Cai
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - LiXin Ke
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - Yan Zhao
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - Jiayun Zhao
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - Huanian Zhang
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - Peie Zheng
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
| | - Lijing Xin
- Animal Imaging and Technology Core, Center for Biomedical ImagingEcole Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - Changchun Ma
- Radiation Oncology DepartmentCancer Hospital of Shantou University Medical CollegeShantouGuangdongChina
| | - Yan Lin
- Radiology Department, Second Affiliated HospitalShantou University Medical CollegeShantou CityGuangdong ProvinceChina
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Wu X, Yang Q, Leng L, Yang P, Zhu Z. Altered metabolic profiles in colon and rectal cancer. Sci Rep 2025; 15:11310. [PMID: 40175601 PMCID: PMC11965280 DOI: 10.1038/s41598-025-96004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 03/25/2025] [Indexed: 04/04/2025] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumour in worldwide populations. Although colon cancer (CC) and rectal cancer (RC) are often discussed together, there is a global trend towards considering them as two separate disease entities. It is necessary to choice the appropriate treatment for CC and RC based on their own characteristics. Hence, it is a great importance to find effective biomarkers to distinguish CC from RC. In the present study, a total of 343 participants were recruited, including 132 healthy individuals, 101 patients with CC, and 110 patients with RC. The concentrations of 93 metabolites were determined by using a combination of dried blood spot sampling and direct infusion mass spectrometry technology. Multiple algorithms were applied to characterize altered metabolic profiles in CC and RC. Significantly altered metabolites were screened for distinguishing RC from CC in training set. A biomarker panel including Glu, C0, C8, C20, Gly/Ala, and C10:1 was tested with tenfold cross-validation and an independent test set, and showed the potential to distinguish between RC and CC. The metabolomics analysis makes contribution to summarize the metabolic differences in RC and CC, which might provide further guidance on novel clinical designs for the two diseases.
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Affiliation(s)
- Xue Wu
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Qi Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Li Leng
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China
| | - Peng Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China.
- The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550003, Guizhou, China.
| | - Zhitu Zhu
- Liaoning Provincial Key Laboratory of Clinical Oncology Metabonomics, Jinzhou Medical University, Jinzhou, China.
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, China.
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Sun L, Wang J, Yu H, Zhu X, Zhang J, Hu J, Yan Y, Zhang X, Zhu Y, Jiang G, Ding M, Zhang P, Zhang L. Selective inhibition of TGF-β-induced epithelial-mesenchymal transition overcomes chemotherapy resistance in high-risk lung squamous cell carcinoma. Commun Biol 2025; 8:152. [PMID: 39893253 PMCID: PMC11787392 DOI: 10.1038/s42003-025-07595-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 01/22/2025] [Indexed: 02/04/2025] Open
Abstract
Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer, and it demonstrates limited treatment options and worse survival. Identifications of a prognostic model and chemoresistance mechanism can be helpful for improving stratification and guiding therapy decisions. The integrative development of machine learning-based models reveals a random survival forest (RSF) prognostic model for LUSC. The 12-gene RSF model exhibits high prognostic power in more than 1,000 LUSC patients. High-risk LUSC patients are associated with worse survival and the activation of the epithelial-mesenchymal transition pathway. Additionally, high-risk LUSC patients are resistant to docetaxel or vinorelbine treatment. In vitro and in vivo drug sensitivity experiments indicates that high-risk HCC15/H226 tumour cells and cell line-derived xenograft models are more resistant to vinorelbine treatment. Furthermore, the combination of chemotherapy with transforming growth factor-β inhibition augments antitumour responses in LUSC tumours. Our study provides valuable insights into prognosis stratification and the development of therapeutic strategies for LUSC.
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Affiliation(s)
- Liangdong Sun
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jue Wang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huansha Yu
- Department of Animal Experimental Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinsheng Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Junjie Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yilv Yan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xun Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuming Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Gening Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ming Ding
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Lele Zhang
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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Zhu M, Hu Y, Gu Y, Lin X, Jiang X, Gong C, Fang Z. Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer. Am J Cancer Res 2025; 15:233-247. [PMID: 39949925 PMCID: PMC11815375 DOI: 10.62347/zsoo2247] [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: 11/09/2024] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.
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Affiliation(s)
- Minjing Zhu
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Yanyan Hu
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Yangjia Gu
- Chinese Medicine, Changchun University of Science and TechnologyChangchun 130600, Jilin, China
| | - Xuedan Lin
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Xiang Jiang
- Department of Gastroenterology, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Chaoju Gong
- Central Laboratory, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhou 221000, Jiangsu, China
| | - Zejun Fang
- Central Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
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Che L, Liu L, Xu M, Fan Z, Niu L, Chen Y, Chang X, Zhou P, Li M, Deng H, Chen W. Valine metabolite, 3-hydroxyisobutyrate, promotes lipid metabolism and cell proliferation in porcine mammary gland epithelial cells. Front Nutr 2025; 11:1524738. [PMID: 39867557 PMCID: PMC11757131 DOI: 10.3389/fnut.2024.1524738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 12/17/2024] [Indexed: 01/28/2025] Open
Abstract
Improving mammary gland epithelial cells proliferation through nutrition is an important approach for enhancing sow milk production and piglet growth. An intermediate metabolite of valine, 3-hydroxyisobutyrate (3-HIB), regulates cellular lipid metabolism. In the present study, we investigated the effects of 3-HIB on porcine mammary gland epithelial cells proliferation and lipid metabolism. The addition of an appropriate concentration of 3-HIB significantly increased mammary gland epithelial cell proliferation and the expression of proteins associated with cell proliferation. Compared to the control group, the addition of 0.4-0.8 mM 3-HIB increased the expression levels of mTOR signaling pathway-related proteins and the cell cycle protein, Cyclin D1, while inhibiting the expression of the cell cycle arrest protein, P27. The addition of 0.8 mM 3-HIB increased the triglyceride and lipid droplet content in the cells. The addition of 3-HIB increased the expression of proteins related to de novo fatty acid synthesis and transport, resulting in a marked increase in most polyunsaturated fatty acids in the 3-HIB-added group. Compared to the control group, the addition of 0.8 mM 3-HIB increased the expression levels of the fatty acid oxidation-related proteins, ACSL and CAD, ultimately increasing cellular ATP synthesis. In summary, the addition of 0.8 mM 3-HIB to porcine mammary gland epithelial cells promotes cell proliferation by enhancing lipid metabolism and the expression of cell proliferation-related proteins.
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Affiliation(s)
- Long Che
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
- Henan Swine Biobreeding Research Institute, Zhengzhou, Henan, China
| | - Le Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Mengmeng Xu
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Zongze Fan
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
| | - Lizhu Niu
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Yujie Chen
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Xueyuan Chang
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Pan Zhou
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, China
| | - Mengyun Li
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Hongyu Deng
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China
| | - Wen Chen
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou, China
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Xing W, Zhou Y, Long Q, Yi N, Wang G, Shi R, Huang J, Yin X, Zhu T, Cao S. Multiomic analysis of lactylation and mitochondria-related genes in hepatocellular carcinoma identified MRPL3 as a new prognostic biomarker. Front Oncol 2025; 14:1511958. [PMID: 39868366 PMCID: PMC11757296 DOI: 10.3389/fonc.2024.1511958] [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: 10/15/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Background Recent research has highlighted lactate's crucial role in epigenetic regulation, particularly by influencing histone modifications that drive the initiation and progression of hepatocellular carcinoma (HCC). While mitochondria are known to regulate tumor behavior, the interaction between lactate metabolism and mitochondrial function in cancer tissues remains underexplored. Understanding this relationship may provide deeper insights into tumor metabolic reprogramming and reveal novel therapeutic targets for HCC and other malignancies. Methods We conducted a comprehensive screening of lactylation- and mitochondria-associated genes (LMRGs) in HCC patients, followed by clustering based on these genes. Prognostic outcomes and pathway enrichment were analyzed across the identified clusters. Additionally, we developed a prognostic model based on LMRGs, examining its implications for survival, immune response, and drug sensitivity. In vitro experiments were performed to validate the expression patterns and functional role of MRPL3 in HCC. Results We developed a prognostic model, named the LMRG model, incorporating three key genes: ACACA, MRPL3, and MRPS23. This model revealed significant differences in survival outcomes, immune responses, and drug sensitivity between patients with high and low LMRG scores. MRPL3 was found to be overexpressed in HCC, playing a critical role in tumor growth and metastasis. These results were further validated through in vitro experiments, confirming MRPL3's role in HCC cell proliferation and invasion. Conclusion We created a predictive model, LMRG, and identified MRPL3 as a key biomarker. Our findings suggest that MRPL3 has significant potential as a reliable predictive biomarker for clinical applications in HCC diagnosis and treatment.
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Affiliation(s)
- Wenya Xing
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Yuanzi Zhou
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Qiuzi Long
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Nan Yi
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Gaoyuan Wang
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Rongwei Shi
- Department of General Internal Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Jinlong Huang
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Xindong Yin
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Taiyang Zhu
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Shibing Cao
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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Gao X, Lin Y, Zhang J, Jiang X, Wu R, Zhong D. Causal Effects of Valine on Ovarian Cancer: A Bidirectional Mendelian Randomization Analysis. Nutr Cancer 2025; 77:405-413. [PMID: 39745021 DOI: 10.1080/01635581.2024.2445870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/21/2025]
Abstract
BACKGROUND Ovarian cancer is a lethal female cancer with a rising incidence that is often diagnosed late due to a lack of symptoms, affecting survival and quality of life. Studies suggest that dietary factors, especially the levels of branched-chain amino acids such as valine, may influence its development. While valine is essential for metabolism, its specific role in ovarian cancer remains unclear, necessitating further research. METHODS This study aimed to elucidate the causal relationship between valine and OC through a bidirectional Mendelian randomization (MR) approach. Data were sourced from the IEU OpenGWAS project, encompassing genome-wide association statistics for valine (N = 115,048) and OC (Ncase = 1,218, Ncontrol = 198,523) among European participants. Independent genetic variants associated with each phenotype at genome-wide significance were employed as instrumental variables (IVs). The primary analysis utilized the inverse variance weighted (IVW) method for two-sample MR analysis. MR‒Egger regression was applied to adjust for potential pleiotropy, whereas the weighted median method provided robust causal estimates under the assumption of valid IVs. Sensitivity analyses, including leave-one-out (LOO) analysis, heterogeneity tests, and horizontal pleiotropy assessments, were conducted to ensure the robustness of the findings. RESULTS The results revealed a significant causal relationship between valine and OC, identifying valine as a risk factor for OC (p = 0.043, 95% CI = 1.00008-1.00491, OR = 1.00249) in the forward MR analysis. Sensitivity analyses confirmed the absence of heterogeneity (Q_p value >0.05) and horizontal pleiotropy (p > 0.05), and LOO analysis validated the stability of the results. Conversely, reverse MR analysis revealed no causal effect of OC on valine levels (p = 0.875, 95% CI = 0.34125-2.51495, OR = 1.08528). CONCLUSIONS These findings reveal a causal link between high valine levels and an increased OC risk. This research highlights the monitoring of valine levels as a preventive strategy and the significance of valine metabolism in OC. Future studies are needed to investigate the mechanisms and interventions for reducing risk, offering insights for clinical practice and public health initiatives in OC prevention.
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Affiliation(s)
- Xinyan Gao
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yanling Lin
- Department of Obstetrics and Gynecology, Fujian Provincial Hospital, Clinical Medical School of Fujian Medical University, Fuzhou, Fujian, China
| | - Jun Zhang
- Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiaoxiang Jiang
- Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Riping Wu
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Dongta Zhong
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
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Yuan X, Yu B, Ding H, Li H, Wang Q, Lin L, Zhang W, Fang X. Novel lipid metabolism factor HIBCH inhibitor synergizes with doxorubicin to suppress osteosarcoma growth and impacts clinical prognosis in osteosarcoma patients. J Bone Oncol 2024; 49:100652. [PMID: 39687213 PMCID: PMC11646752 DOI: 10.1016/j.jbo.2024.100652] [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: 08/29/2024] [Revised: 11/04/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Background Osteosarcoma (OS) is a highly malignant primary bone tumor primarily affecting children and adolescents. Despite advancements in therapeutic strategies, long-term survival rates for OS remain unfavorable, especially in advanced or recurrent cases. Emerging evidence has noted the involvement of lipid metabolism dysregulation in OS progression, but the specific mechanisms remain unclear. Methods A risk model incorporating lipid metabolism-related genes was established to stratify OS patients into high-risk and low-risk groups. Functional assays were conducted to assess the role of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in OS cell activities. Ultra-fast liquid chromatography-mass spectrometry was adopted to analyze the impact of HIBCH on OS cell metabolism. Moreover, the combined effect of HIBCH inhibitor SBF-1 with doxorubicin (DOX) was evaluated through in vitro studies and mouse xenograft models. Results HIBCH was identified as a key gene involved in the malignant behaviors of OS cells. HIBCH knockdown disrupted tricarboxylic acid (TCA) cycle activity and reduced oxidative phosphorylation in OS cells. SBF-1 showed synergistic effects with DOX in inhibiting malignant phenotypes of OS cells by modulating the Akt-mTOR pathway. In vivo experiments demonstrated that the combination of SBF-1 and DOX significantly suppressed tumor growth in mouse xenograft models. Conclusions This study reveals the critical role of lipid metabolism in OS progression and suggests a new therapeutic strategy against chemotherapy resistance in OS based on the synergistic combination of SBF-1 with DOX.
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Affiliation(s)
- Xuhui Yuan
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Bo Yu
- Department of Orthopedic, Huaqiao Hospital, Jinan University, Guangzhou, China
| | - Haiqi Ding
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Hongyan Li
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Qijing Wang
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic, Affiliated Mindong of Fujian Medical University, Fuan, China
| | - Lan Lin
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Wenming Zhang
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Xinyu Fang
- Department of Orthopaedic Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Orthopaedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Fujian Provincial Institute of Orthopedics, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
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He Y, Cai P, Hu A, Li J, Li X, Dang Y. The role of 1400 plasma metabolites in gastric cancer: A bidirectional Mendelian randomization study and metabolic pathway analysis. Medicine (Baltimore) 2024; 103:e40612. [PMID: 39612432 PMCID: PMC11608735 DOI: 10.1097/md.0000000000040612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 11/01/2024] [Indexed: 12/01/2024] Open
Abstract
While observational studies have illustrated correlations between plasma metabolites and gastric cancer (GC), the causal association between the 2 is still unclear. Our study aims to delineate the bidirectional relationship between plasma metabolites and GC and find potential metabolic pathways. We undertook a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationship, specificity, and direction of association between 1400 plasma metabolites and GC. The GWAS data for metabolites was obtained from a cohort of 8299 European individuals. And the GC's GWAS data was from FinnGen Consortium with 2384 European individuals, and the GWAS catalog with 1029 European ancestry cases for validation. Causal estimates were primarily calculated by the inverse-variance weighted (IVW) method. To ensure robustness, we performed comprehensive sensitivity analyses to assess heterogeneity and address concerns regarding horizontal pleiotropy. We validated the forward relationship between metabolites and GC from another database and implemented meta-analysis. Furthermore, we conducted metabolic enrichment and pathway analysis of these causal metabolites using MetaboAnalyst5.0/6.0 with the database of Kyoto Encyclopedia of Genes and Genomes. All statistical analysis was carried out using R software. Metabolites like 2s, 3R-dihydroxybutyrate, 4-acetamidobutanoate, ferulic acid 4-sulfate and methyl indole-3-acetate was proven positively linked with the development of GC. Asparagine, glucose to maltose ratio, glycohyocholate, Gulonate levels, linoleoyl ethanolamide and Spermidine to (N(1) + N(8))-acetylspermidine ratio was proven to be negatively associated with GC. Moreover, linoleic acid, histidine, glutamine, bilirubin, Succinate to proline ratio were found to be potentially linked to the development of GC. Furthermore, our analysis identified 18 significant metabolic pathways, including Arginine and proline metabolism (P < .009) and Valine, leucine, and isoleucine biosynthesis (P < .031). Our findings offer evidence supporting potential casual relations between multiple plasma metabolites and GC. These findings may offer great potential for future application of these biomarkers in GC screening and clinical prevention strategies.
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Affiliation(s)
- Yihao He
- Nanjing Medical University, Nanjing, China
| | | | - Anchi Hu
- Nanjing Medical University, Nanjing, China
| | - Jiali Li
- Nanjing Medical University, Nanjing, China
| | - Xuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Hermawan A, Windarsih A, Putri DDP, Fatimah N. LC-HRMS-based global metabolomics profiling unravels the distinct metabolic signature of lapatinib-resistant and trastuzumab-resistant HER2+ breast cancer cells. J Pharm Biomed Anal 2024; 253:116528. [PMID: 39461067 DOI: 10.1016/j.jpba.2024.116528] [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: 03/31/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/29/2024]
Abstract
The effectiveness of lapatinib (LAP) and trastuzumab (TRZ), the first-line therapies for HER2+ breast cancer, has been limited owing to the development of acquired resistance in patients with HER2+. This study aimed to investigate the alterations in metabolic signatures in LAP-resistant HCC1954 and TRZ-resistant HCC1954 and pathways in human HER2+ breast cancer cells using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and enrichment analysis. The HCC1954 parental cells were sequentially treated 13 rounds with LAP or TRZ to develop resistant cells and then tested for their cytotoxicity using the MTT assay. Metabolites were prepared from HCC1954 parental (MBXWT), HCC1954-LAP (MBXLAP), and HCC1954-TRZ (MBXTRZ) cells prior to LC-HRMS, chemometric, enrichment, and joint pathway analyses. LAP- and TRZ-resistant cells were successfully developed from HCC1954, and 29 and 17 differentially expressed metabolites (DEMs) were identified between MBXWT-MBXLAP and MBXWT-MBXTRZ, respectively. The analysis of DEMs between MBXWT and MBXLAP revealed significant enrichment in D-amino acid metabolism, while MBXWT and MBXTRZ identified valine, leucine, isoleucine biosynthesis, ascorbate, and aldarate metabolism. Joint pathway enrichment analysis of LAP-resistant DEMs and differentially expressed genes (DEGs) showed enrichment in glutathione metabolism, while that of TRZ-resistance and DEGs showed enrichment in carbohydrate metabolism, namely pentose and glucuronate interconversions, starch and sucrose metabolism, and galactose metabolism. The findings from this study indicate considerable metabolic changes in LAP- and TRZ-resistant HCC1954 cells, which are crucial for understanding the resistance mechanisms and developing strategies to overcome these problems.
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Affiliation(s)
- Adam Hermawan
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia; Laboratory of Advanced Pharmaceutical Sciences. APSLC Building, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia; Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia.
| | - Anjar Windarsih
- Research Center for Food Technology and Processing (PRTPP), National Research and Innovation Agency (BRIN), Gunung Kidul, Yogyakarta 55861, Indonesia
| | - Dyaningtyas Dewi Pamungkas Putri
- Laboratory of Advanced Pharmaceutical Sciences. APSLC Building, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia; Laboratory of Pharmacology and Toxicology, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia; Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia
| | - Nurul Fatimah
- Laboratory of Advanced Pharmaceutical Sciences. APSLC Building, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia
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Li Y, Miao Y, Feng Q, Zhu W, Chen Y, Kang Q, Wang Z, Lu F, Zhang Q. Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study. Front Endocrinol (Lausanne) 2024; 15:1401531. [PMID: 39280009 PMCID: PMC11392782 DOI: 10.3389/fendo.2024.1401531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/16/2024] [Indexed: 09/18/2024] Open
Abstract
Background Mitochondrial dysfunction plays a crucial role in Type 2 Diabetes Mellitus (T2DM) and its complications. However, the genetic pathophysiology remains under investigation. Through multi-omics Mendelian Randomization (MR) and colocalization analyses, we identified mitochondrial-related genes causally linked with T2DM and its complications. Methods Summary-level quantitative trait loci data at methylation, RNA, and protein levels were retrieved from European cohort studies. GWAS summary statistics for T2DM and its complications were collected from the DIAGRAM and FinnGen consortiums, respectively. Summary-data-based MR was utilized to estimate the causal effects. The heterogeneity in dependent instrument test assessed horizontal pleiotropy, while colocalization analysis determined whether genes and diseases share the same causal variant. Enrichment analysis, drug target analysis, and phenome-wide MR were conducted to further explore the biological functions, potential drugs, and causal associations with other diseases. Results Integrating evidence from multi-omics, we identified 18 causal mitochondrial-related genes. Enrichment analysis revealed they were not only related to nutrient metabolisms but also to the processes like mitophagy, autophagy, and apoptosis. Among these genes, Tu translation elongation factor mitochondrial (TUFM), 3-hydroxyisobutyryl-CoA hydrolase (HIBCH), and iron-sulfur cluster assembly 2 (ISCA2) were identified as Tier 1 genes, showing causal links with T2DM and strong colocalization evidence. TUFM and ISCA2 were causally associated with an increased risk of T2DM, while HIBCH showed an inverse causal relationship. The causal associations and colocalization effects for TUFM and HIBCH were validated in specific tissues. TUFM was also found to be a risk factor for microvascular complications in T2DM patients including retinopathy, nephropathy, and neuropathy. Furthermore, drug target analysis and phenome-wide MR underscored their significance as potential therapeutic targets. Conclusions This study identified 18 mitochondrial-related genes causally associated with T2DM at multi-omics levels, enhancing the understanding of mitochondrial dysfunction in T2DM and its complications. TUFM, HIBCH, and ISCA2 emerge as potential therapeutic targets for T2DM and its complications.
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Affiliation(s)
- Yang Li
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yahu Miao
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qing Feng
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Weixi Zhu
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yijing Chen
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qingqing Kang
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhen Wang
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fangting Lu
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiu Zhang
- Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Bidgood CL, Philp LK, Rockstroh A, Lehman M, Nelson CC, Sadowski MC, Gunter JH. Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer. Cell Death Dis 2024; 15:513. [PMID: 39025852 PMCID: PMC11258138 DOI: 10.1038/s41419-024-06893-2] [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: 01/24/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/20/2024]
Abstract
Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.
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Affiliation(s)
- Charles L Bidgood
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia.
| | - Lisa K Philp
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia
| | - Anja Rockstroh
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia
| | - Melanie Lehman
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia
- University of British Columbia, Vancouver Prostate Centre, Department of Urologic Sciences, Vancouver, BC, Canada
| | - Colleen C Nelson
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia
| | - Martin C Sadowski
- University of Bern, Institute for Tissue Medicine and Pathology, Bern, Switzerland
| | - Jennifer H Gunter
- Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia.
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Peng Z, Ahsan N, Yang Z. Proteomics Analysis of Interactions between Drug-Resistant and Drug-Sensitive Cancer Cells: Comparative Studies of Monoculture and Coculture Cell Systems. J Proteome Res 2024; 23:2608-2618. [PMID: 38907724 PMCID: PMC11425778 DOI: 10.1021/acs.jproteome.4c00338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2024]
Abstract
Cell-cell interactions, which allow cells to communicate with each other through molecules in their microenvironment, are critical for the growth, health, and functions of cells. Previous studies show that drug-resistant cells can interact with drug-sensitive cells to elevate their drug resistance level, which is partially responsible for cancer recurrence. Studying protein targets and pathways involved in cell-cell communication provides essential information for fundamental cell biology studies and therapeutics of human diseases. In the current studies, we performed direct coculture and indirect coculture of drug-resistant and drug-sensitive cell lines, aiming to investigate intracellular proteins responsible for cell communication. Comparative studies were carried out using monoculture cells. Shotgun bottom-up proteomics results indicate that the P53 signaling pathway has a strong association with drug resistance mechanisms, and multiple TP53-related proteins were upregulated in both direct and indirect coculture systems. In addition, cell-cell communication pathways, including the phagosome and the HIF-signaling pathway, contribute to both direct and indirect coculture systems. Consequently, AK3 and H3-3A proteins were identified as potential targets for cell-cell interactions that are relevant to drug resistance mechanisms. We propose that the P53 signaling pathway, in which mitochondrial proteins play an important role, is responsible for inducing drug resistance through communication between drug-resistant and drug-sensitive cancer cells.
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Affiliation(s)
- Zongkai Peng
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Nagib Ahsan
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
- Mass Spectrometry, Proteomics and Metabolomics Core Facility, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, Oklahoma 73019, United States
| | - Zhibo Yang
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States
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15
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Jia Y, Chen X, Guo H, Zhang B, Liu B. Comprehensive characterization of β-alanine metabolism-related genes in HCC identified a novel prognostic signature related to clinical outcomes. Aging (Albany NY) 2024; 16:7073-7100. [PMID: 38637116 PMCID: PMC11087131 DOI: 10.18632/aging.205744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 02/02/2024] [Indexed: 04/20/2024]
Abstract
Hepatocellular carcinoma (HCC) stands out as the most prevalent type of liver cancer and a significant contributor to cancer-related fatalities globally. Metabolic reprogramming, particularly in glucose, lipid, and amino acid metabolism, plays a crucial role in HCC progression. However, the functions of β-alanine metabolism-related genes (βAMRGs) in HCC remain understudied. Therefore, a comprehensive evaluation of βAMRGs is required, specifically in HCC. Initially, we explored the pan-cancer landscape of βAMRGs, integrating expression profiles, prognostic values, mutations, and methylation levels. Subsequently, scRNA sequencing results indicated that hepatocytes had the highest scores of β-alanine metabolism. In the process of hepatocyte carcinogenesis, metabolic pathways were further activated. Using βAMRGs scores and expression profiles, we classified HCC patients into three subtypes and examined their prognosis and immune microenvironments. Cluster 3, characterized by the highest βAMRGs scores, displayed the best prognosis, reinforcing β-alanine's significant contribution to HCC pathophysiology. Notably, immune microenvironment, metabolism, and cell death modes significantly varied among the β-alanine subtypes. We developed and validated a novel prognostic panel based on βAMRGs and constructed a nomogram incorporating risk degree and clinicopathological characteristics. Among the model genes, EHHADH has been identified as a protective protein in HCC. Its expression was notably downregulated in tumors and exhibited a close correlation with factors such as tumor staging, grading, and prognosis. Immunohistochemical experiments, conducted using HCC tissue microarrays, substantiated the validation of its expression levels. In conclusion, this study uncovers β-alanine's significant role in HCC for the first time, suggesting new research targets and directions for diagnosis and treatment.
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Affiliation(s)
- Yi Jia
- Department of General Surgery, Xinhua Hospital of Dalian University, Dalian, Liaoning, China
| | - Xu Chen
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hui Guo
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Biao Zhang
- Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bin Liu
- Department of General Surgery, Xinhua Hospital of Dalian University, Dalian, Liaoning, China
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Da J, Di X, Xie Y, Li J, Zhang L, Liu Y. Recent advances in nanomedicine for metabolism-targeted cancer therapy. Chem Commun (Camb) 2024; 60:2442-2461. [PMID: 38321983 DOI: 10.1039/d3cc05858a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Metabolism denotes the sum of biochemical reactions that maintain cellular function. Different from most normal differentiated cells, cancer cells adopt altered metabolic pathways to support malignant properties. Typically, almost all cancer cells need a large number of proteins, lipids, nucleotides, and energy in the form of ATP to support rapid division. Therefore, targeting tumour metabolism has been suggested as a generic and effective therapy strategy. With the rapid development of nanotechnology, nanomedicine promises to have a revolutionary impact on clinical cancer therapy due to many merits such as targeting, improved bioavailability, controllable drug release, and potentially personalized treatment compared to conventional drugs. This review comprehensively elucidates recent advances of nanomedicine in targeting important metabolites such as glucose, glutamine, lactate, cholesterol, and nucleotide for effective cancer therapy. Furthermore, the challenges and future development in this area are also discussed.
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Affiliation(s)
- Jun Da
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - XinJia Di
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - YuQi Xie
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - JiLi Li
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - LiLi Zhang
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
| | - YanLan Liu
- Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
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Xu Z, Huang Y, Hu C, Du L, Du YA, Zhang Y, Qin J, Liu W, Wang R, Yang S, Wu J, Cao J, Zhang J, Chen GP, Lv H, Zhao P, He W, Wang X, Xu M, Wang P, Hong C, Yang LT, Xu J, Chen J, Wei Q, Zhang R, Yuan L, Qian K, Cheng X. Efficient plasma metabolic fingerprinting as a novel tool for diagnosis and prognosis of gastric cancer: a large-scale, multicentre study. Gut 2023; 72:2051-2067. [PMID: 37460165 PMCID: PMC11883865 DOI: 10.1136/gutjnl-2023-330045] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 06/26/2023] [Indexed: 10/08/2023]
Abstract
OBJECTIVE Metabolic biomarkers are expected to decode the phenotype of gastric cancer (GC) and lead to high-performance blood tests towards GC diagnosis and prognosis. We attempted to develop diagnostic and prognostic models for GC based on plasma metabolic information. DESIGN We conducted a large-scale, multicentre study comprising 1944 participants from 7 centres in retrospective cohort and 264 participants in prospective cohort. Discovery and verification phases of diagnostic and prognostic models were conducted in retrospective cohort through machine learning and Cox regression of plasma metabolic fingerprints (PMFs) obtained by nanoparticle-enhanced laser desorption/ionisation-mass spectrometry (NPELDI-MS). Furthermore, the developed diagnostic model was validated in prospective cohort by both NPELDI-MS and ultra-performance liquid chromatography-MS (UPLC-MS). RESULTS We demonstrated the high throughput, desirable reproducibility and limited centre-specific effects of PMFs obtained through NPELDI-MS. In retrospective cohort, we achieved diagnostic performance with areas under curves (AUCs) of 0.862-0.988 in the discovery (n=1157 from 5 centres) and independent external verification dataset (n=787 from another 2 centres), through 5 different machine learning of PMFs, including neural network, ridge regression, lasso regression, support vector machine and random forest. Further, a metabolic panel consisting of 21 metabolites was constructed and identified for GC diagnosis with AUCs of 0.921-0.971 and 0.907-0.940 in the discovery and verification dataset, respectively. In the prospective study (n=264 from lead centre), both NPELDI-MS and UPLC-MS were applied to detect and validate the metabolic panel, and the diagnostic AUCs were 0.855-0.918 and 0.856-0.916, respectively. Moreover, we constructed a prognosis scoring system for GC in retrospective cohort, which can effectively predict the survival of GC patients. CONCLUSION We developed and validated diagnostic and prognostic models for GC, which also contribute to advanced metabolic analysis towards diseases, including but not limited to GC.
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Affiliation(s)
- Zhiyuan Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Yida Huang
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Can Hu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
| | - Lingbin Du
- Office of Cancer Center, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yi-An Du
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yanqiang Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jiangjiang Qin
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Wanshan Liu
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruimin Wang
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shouzhi Yang
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiao Wu
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Cao
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Juxiang Zhang
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Gui-Ping Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Hang Lv
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Ping Zhao
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital, Chengdu, China
| | - Weiyang He
- Department of Gastrointestinal Surgery, Sichuan Cancer Hospital, Chengdu, China
| | - Xiaoliang Wang
- Department of General Surgery, Fenghua People's Hospital, Ningbo, China
| | - Min Xu
- Department of Gastroenterology, Tiantai People's Hospital, Taizhou, China
| | - Pingfang Wang
- Department of Gastroenterology, Xinchang People's Hospital, Shaoxing, China
| | - Chuanshen Hong
- Department of General Surgery, Daishan People's Hospital, Zhoushan, China
| | - Li-Tao Yang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jingli Xu
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jiahui Chen
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Qing Wei
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ruolan Zhang
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Li Yuan
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Kun Qian
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Gynecologic Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiangdong Cheng
- Department of Gastric Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- Office of Cancer Center, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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Rodríguez-Vázquez GO, Diaz-Quiñones AO, Chorna N, Salgado-Villanueva IK, Tang J, Ortiz WIS, Maldonado HM. Synergistic interactions of cytarabine-adavosertib in leukemic cell lines proliferation and metabolomic endpoints. Biomed Pharmacother 2023; 166:115352. [PMID: 37633054 PMCID: PMC10530627 DOI: 10.1016/j.biopha.2023.115352] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/09/2023] [Accepted: 08/19/2023] [Indexed: 08/28/2023] Open
Abstract
Drug synergy allows reduced dosing, side effects and tolerance. Optimization of drug synergy chemotherapy is fundamental in acute lymphocytic leukemia and other cancers. This study aimed to analyze the pharmacodynamic synergy between the anti-metabolite cytarabine and WEE1 inhibitor adavosertib on acute leukemia cell lines CCRF-CEM and Jurkat. In both cell lines analysis of concentration-inhibition curves of adavosertib-cytarabine combinations and synergy matrixes supported mutually synergistic drug interactions. Overall mean ( ± SD) synergy scores were higher in Jurkat than CCRF-CEM: Jurkat, ZIP 22.51 ± 1.1, Bliss 22.49 ± 1.1, HSA 23.44 ± 1.0, Loewe 14.16 ± 1.2; and, CCRF-CEM, ZIP 9.17 ± 1.9, Bliss 8.13 ± 2.1, HSA 11.48 ± 1.9 and Loewe 4.99 ± 1.8. Jurkat also surpassed CCRF-CEM in high-degree synergistic adavosertib-cytarabine interactions with mean across-models synergy values of ∼89.1% ± 2.9 for 63 nM cytarabine-97 nM adavosertib (91.4% inhibition synergy barometer). Combination sensitivity scores scatter plots confirmed combination's synergy efficacy. This combined approach permitted identification and prioritization of 63 nM cytarabine-97 nM adavosertib for multiple endpoints analysis. This combination did not affect PBMC viability, while exhibiting Jurkat selective synergy. Immunoblots also revealed Jurkat selective synergistically increased γH2AX phosphorylation, while CDC2 phosphorylation effects were attributed to adavosertib's WEE1 inhibition. In conclusion, the high synergistic efficacy combination of cytarabine (63 nM) and adavosertib (97 nM) was associated with remarkable alterations in metabolites related to the Krebs cycle in Jurkat. The metabolic pathways and processes are related to gluconeogenesis, amino acids, nucleotides, glutathione, electron transport and Warburg effect. All above relate to cell survival, apoptosis, and cancer progression. Our findings could pave the way for novel biomarkers in treatment, diagnosis, and prognosis of leukemia and other cancers.
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Affiliation(s)
- Gabriel O Rodríguez-Vázquez
- Pharmacology Department, Universidad Central del Caribe, School of Medicine, PO Box 60327, Bayamón, PR 00960-6032, USA
| | - Adriana O Diaz-Quiñones
- Pharmacology Department, Universidad Central del Caribe, School of Medicine, PO Box 60327, Bayamón, PR 00960-6032, USA
| | - Nataliya Chorna
- Biochemistry Department, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067, USA
| | - Iris K Salgado-Villanueva
- Pharmacology Department, Universidad Central del Caribe, School of Medicine, PO Box 60327, Bayamón, PR 00960-6032, USA
| | - Jing Tang
- Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki 00290, Finland; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki 00290, Finland
| | - Walter I Silva Ortiz
- Physiology Department, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067, USA.
| | - Héctor M Maldonado
- Pharmacology Department, Universidad Central del Caribe, School of Medicine, PO Box 60327, Bayamón, PR 00960-6032, USA
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Nunes SC, Sousa J, Silva F, Silveira M, Guimarães A, Serpa J, Félix A, Gonçalves LG. Peripheral Blood Serum NMR Metabolomics Is a Powerful Tool to Discriminate Benign and Malignant Ovarian Tumors. Metabolites 2023; 13:989. [PMID: 37755269 PMCID: PMC10537270 DOI: 10.3390/metabo13090989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/29/2023] [Accepted: 08/31/2023] [Indexed: 09/28/2023] Open
Abstract
Ovarian cancer is the major cause of death from gynecological cancer and the third most common gynecological malignancy worldwide. Despite a slight improvement in the overall survival of ovarian carcinoma patients in recent decades, the cure rate has not improved. This is mainly due to late diagnosis and resistance to therapy. It is therefore urgent to develop effective methods for early detection and prognosis. We hypothesized that, besides being able to distinguish serum samples of patients with ovarian cancer from those of patients with benign ovarian tumors, 1H-NMR metabolomics analysis might be able to predict the malignant potential of tumors. For this, serum 1H-NMR metabolomics analyses were performed, including patients with malignant, benign and borderline ovarian tumors. The serum metabolic profiles were analyzed by multivariate statistical analysis, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) methods. A metabolic profile associated with ovarian malignant tumors was defined, in which lactate, 3-hydroxybutyrate and acetone were increased and acetate, histidine, valine and methanol were decreased. Our data support the use of 1H-NMR metabolomics analysis as a screening method for ovarian cancer detection and might be useful for predicting the malignant potential of borderline tumors.
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Affiliation(s)
- Sofia C. Nunes
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Lisboa, Portugal; (S.C.N.); (J.S.); (A.F.)
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Joana Sousa
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB NOVA), Avenida da República (EAN), 2780-157 Oeiras, Portugal
| | - Fernanda Silva
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Lisboa, Portugal; (S.C.N.); (J.S.); (A.F.)
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Margarida Silveira
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - António Guimarães
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Jacinta Serpa
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Lisboa, Portugal; (S.C.N.); (J.S.); (A.F.)
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Ana Félix
- iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria 130, 1169-056 Lisboa, Portugal; (S.C.N.); (J.S.); (A.F.)
- Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Luís G. Gonçalves
- Instituto de Tecnologia Química e Biológica António Xavier (ITQB NOVA), Avenida da República (EAN), 2780-157 Oeiras, Portugal
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Yang L, Wang X, Liu J, Liu X, Li S, Zheng F, Dong Q, Xu S, Xiong J, Fu B. Prognostic and tumor microenvironmental feature of clear cell renal cell carcinoma revealed by m6A and lactylation modification-related genes. Front Immunol 2023; 14:1225023. [PMID: 37638005 PMCID: PMC10450969 DOI: 10.3389/fimmu.2023.1225023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023] Open
Abstract
Background Both lactylation and m6A modification have important implications for the development of clear cell renal cell carcinoma (ccRCC), and we aimed to use crosstalk genes of both to reveal the prognostic and immunological features of ccRCC. Methods Our first step was to look for lactylation-related genes that differed between normal and tumor tissues, and then by correlation analysis, we found the genes associated with M6A. Following that, ccRCC subtypes will be identified and risk models will be constructed to compare the prognosis and tumor microenvironment among different subgroups. A nomogram was constructed to predict the prognosis of ccRCC, and in vitro, experiments were conducted to validate the expression and function of key genes. Results We screened 100 crosstalk genes and identified 2 ccRCC subtypes. A total of 11 prognostic genes were screened for building a risk model. we observed higher immune scores, elevated tumor mutational burden, and microsatellite instability scores in the high-risk group. Therefore, individuals classified as high-risk would derive greater benefits from immunotherapy. The nomogram's ability to predict overall survival with a 1-year AUC of 0.863 demonstrates its significant practical utility. In addition, HIBCH was identified as a potential therapeutic target and its expression and function were verified by in vitro experiments. Conclusion In addition to developing a precise prognostic nomogram for patients with ccRCC, our study also discovered the potential of HIBCH as a biomarker for the disease.
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Affiliation(s)
| | | | | | | | | | | | | | - Songhui Xu
- Department of Urology, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Xiong
- Department of Urology, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bin Fu
- Department of Urology, First Affiliated Hospital of Nanchang University, Nanchang, China
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21
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Shen L, Huang H, Li J, Chen W, Yao Y, Hu J, Zhou J, Huang F, Ni C. Exploration of prognosis and immunometabolism landscapes in ER+ breast cancer based on a novel lipid metabolism-related signature. Front Immunol 2023; 14:1199465. [PMID: 37469520 PMCID: PMC10352658 DOI: 10.3389/fimmu.2023.1199465] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/19/2023] [Indexed: 07/21/2023] Open
Abstract
Introduction Lipid metabolic reprogramming is gaining attention as a hallmark of cancers. Recent mounting evidence indicates that the malignant behavior of breast cancer (BC) is closely related to lipid metabolism. Here, we focus on the estrogen receptor-positive (ER+) subtype, the most common subgroup of BC, to explore immunometabolism landscapes and prognostic significance according to lipid metabolism-related genes (LMRGs). Methods Samples from The Cancer Genome Atlas (TCGA) database were used as training cohort, and samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Gene Expression Omnibus (GEO) datasets and our cohort were applied for external validation. The survival-related LMRG molecular pattern and signature were constructed by unsupervised consensus clustering and least absolute shrinkage and selection operator (LASSO) analysis. A lipid metabolism-related clinicopathologic nomogram was established. Gene enrichment and pathway analysis were performed to explore the underlying mechanism. Immune landscapes, immunotherapy and chemotherapy response were further explored. Moreover, the relationship between gene expression and clinicopathological features was assessed by immunohistochemistry. Results Two LMRG molecular patterns were identified and associated with distinct prognoses and immune cell infiltration. Next, a prognostic signature based on nine survival-related LMRGs was established and validated. The signature was confirmed to be an independent prognostic factor and an optimal nomogram incorporating age and T stage (AUC of 5-year overall survival: 0.778). Pathway enrichment analysis revealed differences in immune activities, lipid biosynthesis and drug metabolism by comparing groups with low- and high-risk scores. Further exploration verified different immune microenvironment profiles, immune checkpoint expression, and sensitivity to immunotherapy and chemotherapy between the two groups. Finally, arachidonate 15-lipoxygenase (ALOX15) was selected as the most prominent differentially expressed gene between the two groups. Its expression was positively related to larger tumor size, more advanced tumor stage and vascular invasion in our cohort (n = 149). Discussion This is the first lipid metabolism-based signature with value for prognosis prediction and immunotherapy or chemotherapy guidance for ER+ BC.
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Affiliation(s)
- Lesang Shen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Huanhuan Huang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jiaxin Li
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Wuzhen Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yao Yao
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jianming Hu
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jun Zhou
- Department of Breast Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fengbo Huang
- Department of Pathology, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chao Ni
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, China
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22
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Julca I, Mutwil-Anderwald D, Manoj V, Khan Z, Lai SK, Yang LK, Beh IT, Dziekan J, Lim YP, Lim SK, Low YW, Lam YI, Tjia S, Mu Y, Tan QW, Nuc P, Choo LM, Khew G, Shining L, Kam A, Tam JP, Bozdech Z, Schmidt M, Usadel B, Kanagasundaram Y, Alseekh S, Fernie A, Li HY, Mutwil M. Genomic, transcriptomic, and metabolomic analysis of Oldenlandia corymbosa reveals the biosynthesis and mode of action of anti-cancer metabolites. JOURNAL OF INTEGRATIVE PLANT BIOLOGY 2023. [PMID: 36807520 DOI: 10.1111/jipb.13469] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 02/18/2023] [Indexed: 06/18/2023]
Abstract
Plants accumulate a vast array of secondary metabolites, which constitute a natural resource for pharmaceuticals. Oldenlandia corymbosa belongs to the Rubiaceae family, and has been used in traditional medicine to treat different diseases, including cancer. However, the active metabolites of the plant, their biosynthetic pathway and mode of action in cancer are unknown. To fill these gaps, we exposed this plant to eight different stress conditions and combined different omics data capturing gene expression, metabolic profiles, and anti-cancer activity. Our results show that O. corymbosa extracts are active against breast cancer cell lines and that ursolic acid is responsible for this activity. Moreover, we assembled a high-quality genome and uncovered two genes involved in the biosynthesis of ursolic acid. Finally, we also revealed that ursolic acid causes mitotic catastrophe in cancer cells and identified three high-confidence protein binding targets by Cellular Thermal Shift Assay (CETSA) and reverse docking. Altogether, these results constitute a valuable resource to further characterize the biosynthesis of active metabolites in the Oldenlandia group, while the mode of action of ursolic acid will allow us to further develop this valuable compound.
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Affiliation(s)
- Irene Julca
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | | | - Vaishnervi Manoj
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Zahra Khan
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Soak Kuan Lai
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Lay K Yang
- Shared Analytics, Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore
| | - Ing T Beh
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Jerzy Dziekan
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Yoon P Lim
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore
| | - Shen K Lim
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore
| | - Yee W Low
- Singapore Botanic Gardens, Singapore, 259569, Singapore
| | - Yuen I Lam
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Seth Tjia
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Yuguang Mu
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Qiao W Tan
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Przemyslaw Nuc
- Department of Gene Expression, Faculty of Biology, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, 61-614, Poland
| | - Le M Choo
- Singapore Botanic Gardens, Singapore, 259569, Singapore
| | - Gillian Khew
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
- Singapore Botanic Gardens, Singapore, 259569, Singapore
| | - Loo Shining
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Antony Kam
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - James P Tam
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Zbynek Bozdech
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | | | - Bjoern Usadel
- IBG-4 Bioinformatics, Forschungszentrum Jülich, Jülich, 52428, Germany
| | - Yoganathan Kanagasundaram
- Shared Analytics, Singapore Institute of Food and Biotechnology Innovation (SIFBI), Agency for Science, Technology and Research (A*STAR), Singapore, 138671, Singapore
| | - Saleh Alseekh
- Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam-Golm, 14476, Germany
- Center of Plant Systems Biology and Biotechnology, Plovdiv, 4000, Bulgaria
| | - Alisdair Fernie
- Max-Planck-Institut für Molekulare Pflanzenphysiologie, Potsdam-Golm, 14476, Germany
- Center of Plant Systems Biology and Biotechnology, Plovdiv, 4000, Bulgaria
| | - Hoi Y Li
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
| | - Marek Mutwil
- School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore
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23
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Identification of HIBCH as a Fatty Acid Metabolism-Related Biomarker in Aortic Valve Calcification Using Bioinformatics. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022. [DOI: 10.1155/2022/9558713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Objective. To identify fatty acid metabolism-related biomarkers of aortic valve calcification (AVC) using bioinformatics and to research the role of immune cell infiltration for AVC. Methods. The AVC dataset was retrieved from the Gene Expression Omnibus database. R package is used for differential expression genes analysis and weighted gene coexpression analysis. The differentially coexpressed genes were identified by the Venn diagram, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of differentially coexpressed genes. Functions closely related to AVC were identified by GO and KEGG enrichment analyses of differentially coexpressed genes. Genes related to fatty acid metabolism were retrieved from the Molecular Signatures Database (MSigDB) database. After removing duplicate genes, least absolute shrinkage and selection operator (LASSO) regression analysis, support vector machine recursive feature elimination (SVM-RFE), and random forest were applied to recognize biomarkers related to fatty acid metabolism in AVC. The CIBERSORT tool was used to analyze infiltration of immune cells in normal and AVC samples. Correlations between biomarkers and immune cells were calculated. Finally, HIBCH-related pathway was predicted by single-gene gene set enrichment analysis (GSEA). Results. 2416 differentially expressed genes and one coexpression module were identified. A total of 1473 differentially coexpressed genes were acquired. GO and KEGG enrichment analyses demonstrated that differentially coexpressed genes were closely related to fatty acid metabolism. LASSO regression analysis, SVM-REF, and random forest revealed that 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) was a biomarker of fatty acid metabolism-related genes in AVC. Significant high levels of memory B cells were found in AVC than normal samples, while activated natural killer (NK) cells were significantly low in AVC than normal samples. A significantly positive relevance was observed between HIBCH and activated NK cells, regulatory T cells, monocytes, naïve B cells, activated dendritic cells, resting memory CD4 T cells, resting NK cells, and CD8 T cells. A significantly negative relevance was observed between HIBCH and activated memory CD4 T cells, memory B cells, neutrophils, gamma delta T cells, M0 macrophages, and plasma cells. The single-gene GSEA results suggest that HIBCH may work through the inhibition of multiple immune-related pathways. Conclusion. HIBCH is closely relevant to immune cell infiltration in AVC and could be applied as a diagnostic marker for AVC.
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Zhao J, Zhao X, Yu J, Gao S, Zhang M, Yang T, Liu L. A multi-platform metabolomics reveals possible biomarkers for the early-stage esophageal squamous cell carcinoma. Anal Chim Acta 2022; 1220:340038. [PMID: 35868700 DOI: 10.1016/j.aca.2022.340038] [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: 03/26/2022] [Revised: 05/25/2022] [Accepted: 06/02/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent types of upper gastrointestinal malignancies. This work aimed to identify potential biomarkers for early screening for ESCC and characterize the systemic metabolic disturbances underlying ESCC using multi-platform metabolomics analysis. METHODS We divided 239 patients (the early-stage ESCC patients, n = 132; Healthy controls, n = 107) into discovery and validation sets after matching age and sex. Integrated statistical and multi-platform serum metabolomics analyses were used to screen and validate significant metabolites linked to ESCC patients. RESULTS Multi-platform metabolomics analyses showed that amino acid and lipid metabolism were crucial in the etiology of ESCC. Five metabolites, tryptophan (Trp), citrulline, l-carnitine, lysine, and acetyl-carnitine, were selected as potential biomarkers to establish a diagnosis panel, which showed high accuracy in distinguishing ESCC patients from healthy controls (area under the receiver operating characteristic curve, 0.873, 95% confidence interval [CI]: 0.825-0.925). CONCLUSIONS This work laid the groundwork for understanding the etiology of ESCC. The diagnostic panel showed potential usefulness in early-stage ESCC diagnosis in clinical practice.
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Affiliation(s)
- Jinhui Zhao
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Xinshu Zhao
- The Affiliated Tumor Hospital of Harbin Medical University, Harbin Medical University, Harbin, PR China
| | - Jiaying Yu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Siqi Gao
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Mingjia Zhang
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Tongshu Yang
- The Affiliated Tumor Hospital of Harbin Medical University, Harbin Medical University, Harbin, PR China
| | - Liyan Liu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China.
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Yeoh Y, Low TY, Abu N, Lee PY. Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance. PeerJ 2021; 9:e12338. [PMID: 34733591 PMCID: PMC8544255 DOI: 10.7717/peerj.12338] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/28/2021] [Indexed: 12/13/2022] Open
Abstract
Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.
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Affiliation(s)
- Yeelon Yeoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nadiah Abu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Supruniuk E, Żebrowska E, Chabowski A. Branched chain amino acids-friend or foe in the control of energy substrate turnover and insulin sensitivity? Crit Rev Food Sci Nutr 2021; 63:2559-2597. [PMID: 34542351 DOI: 10.1080/10408398.2021.1977910] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Branched chain amino acids (BCAA) and their derivatives are bioactive molecules with pleiotropic functions in the human body. Elevated fasting blood BCAA concentrations are considered as a metabolic hallmark of obesity, insulin resistance, dyslipidaemia, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease. However, since increased BCAA amount is observed both in metabolically healthy and obese subjects, a question whether BCAA are mechanistic drivers of insulin resistance and its morbidities or only markers of metabolic dysregulation, still remains open. The beneficial effects of BCAA on body weight and composition, aerobic capacity, insulin secretion and sensitivity demand high catabolic potential toward amino acids and/or adequate BCAA intake. On the opposite, BCAA-related inhibition of lipogenesis and lipolysis enhancement may preclude impairment in insulin sensitivity. Thereby, the following review addresses various strategies pertaining to the modulation of BCAA catabolism and the possible roles of BCAA in energy homeostasis. We also aim to elucidate mechanisms behind the heterogeneity of ramifications associated with BCAA modulation.
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Affiliation(s)
- Elżbieta Supruniuk
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Żebrowska
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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Inhibiting BCKDK in triple negative breast cancer suppresses protein translation, impairs mitochondrial function, and potentiates doxorubicin cytotoxicity. Cell Death Discov 2021; 7:241. [PMID: 34526485 PMCID: PMC8443725 DOI: 10.1038/s41420-021-00602-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/25/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Triple-negative breast cancers (TNBCs) are characterized by poor survival, prognosis, and gradual resistance to cytotoxic chemotherapeutics, like doxorubicin (DOX). The clinical utility of DOX is limited by its cardiotoxic and chemoresistant effects that manifest over time. To induce chemoresistance, TNBC rewires oncogenic gene expression and cell signaling pathways. Recent studies have demonstrated that reprogramming of branched-chain amino acids (BCAAs) metabolism facilitates tumor growth and survival. Branched-chain ketoacid dehydrogenase kinase (BCKDK), a regulatory kinase of the rate-limiting enzyme of the BCAA catabolic pathway, is reported to activate RAS/RAF/MEK/ERK signaling to promote tumor cell proliferation. However, it remains unexplored if BCKDK action remodels TNBC proliferation and survival per se and influences susceptibility to DOX-induced genotoxic stress. TNBC cells treated with DOX exhibited reduced BCKDK expression and intracellular BCKAs. Genetic and pharmacological inhibition of BCKDK in TNBC cell lines also showed a similar reduction in intracellular and secreted BCKAs. BCKDK silencing in TNBC cells downregulated mitochondrial metabolism genes, reduced electron complex protein expression, oxygen consumption, and ATP production. Transcriptome analysis of BCKDK silenced cells confirmed dysregulation of mitochondrial metabolic networks and upregulation of the apoptotic signaling pathway. Furthermore, BCKDK inhibition with concurrent DOX treatment exacerbated apoptosis, caspase activity, and loss of TNBC proliferation. Inhibition of BCKDK in TNBC also upregulated sestrin 2 and concurrently decreased mTORC1 signaling and protein synthesis. Overall, loss of BCKDK action in TNBC remodels BCAA flux, reduces protein translation triggering cell death, ATP insufficiency, and susceptibility to genotoxic stress. Proposed mechanism. A Doxorubicin (DOX) targets the BCAA catabolic pathway in TNBCs, by downregulating BCKDK and augmenting clearance of intracellular BCKAs. B Genetic or pharmacological (high BT2 concentration) inhibition of BCKDK results in increased cell death, decreased intracellular BCKAs, dysregulated mitochondrial function, ATP insufficiency, SESN2 activation, and inhibition of mTORC1 signaling and protein synthesis. C BCKDK inhibition (siRNA mediated or low-BT2 concentration) exacerbates DOX-induced cytotoxicity and caspase activity. ![]()
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Li L, Li G, Chen M, Cai R. Astragaloside IV enhances the sensibility of lung adenocarcinoma cells to bevacizumab by inhibiting autophagy. Drug Dev Res 2021; 83:461-469. [PMID: 34499759 DOI: 10.1002/ddr.21878] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 12/24/2022]
Abstract
Bevacizumab (BV) has an inhibitory effect on tumor growth including lung adenocarcinoma. However, its efficacy is greatly affected by drug resistance. Astragaloside IV (AST-IV) is effective in combination with other drugs is effective to treat cancer. This study aimed to investigate the effect of AST-IV on enhancing the sensibility of lung adenocarcinoma cells to BV. A549 cells were treated by different concentrations of BV and AST-IV. Cell viability, cell cycle, and apoptosis were detected by thiazolyl blue tetrazolium bromide (MTT) and flow cytometry, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect the expression levels of autophagy- and apoptosis-related proteins, protein kinase B (AKT), and mammalian target of rapamycin (mTOR). The results showed that BV or AST-IV could inhibit the viability and promote the apoptosis of A549 cells in a concentration-dependent manner. Moreover, BV or AST-IV inhibited Bcl-2 expression and increased the expressions of Bax and Cleaved caspase-3, and promoted apoptosis. BV and AST-IV in combination acted synergistically on viability and apoptosis of A549 cells. However, BV alone down-regulated P62 expression, LC3I/LC3II level, the number of cells arrested at S phase and the phosphorylation levels of AKT and mTOR, but upregulated the number of cells arrested at G0/G1 phase and Beclin1 expression, whereas AST-IV alone could reverse the effect of BV on autophagy-related proteins, the phosphorylation levels of AKT and mTOR. This paper demonstrates that AST-IV enhances the effect of BV on inhibiting proliferation and promoting apoptosis of lung adenocarcinoma cells through inhibiting autophagy pathway.
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Affiliation(s)
- Liang Li
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, China
| | - Gao Li
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, China
| | - Minbiao Chen
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, China
| | - Renzhong Cai
- Department of Thoracic Surgery, Hainan General Hospital, Haikou, China
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30
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Guo Y, Yu H, Song H, He J, Oyebamiji O, Kang H, Ping J, Ness S, Shyr Y, Ye F. MetaGSCA: A tool for meta-analysis of gene set differential coexpression. PLoS Comput Biol 2021; 17:e1008976. [PMID: 33945541 PMCID: PMC8121311 DOI: 10.1371/journal.pcbi.1008976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 05/14/2021] [Accepted: 04/18/2021] [Indexed: 01/24/2023] Open
Abstract
Analyses of gene set differential coexpression may shed light on molecular mechanisms underlying phenotypes and diseases. However, differential coexpression analyses of conceptually similar individual studies are often inconsistent and underpowered to provide definitive results. Researchers can greatly benefit from an open-source application facilitating the aggregation of evidence of differential coexpression across studies and the estimation of more robust common effects. We developed Meta Gene Set Coexpression Analysis (MetaGSCA), an analytical tool to systematically assess differential coexpression of an a priori defined gene set by aggregating evidence across studies to provide a definitive result. In the kernel, a nonparametric approach that accounts for the gene-gene correlation structure is used to test whether the gene set is differentially coexpressed between two comparative conditions, from which a permutation test p-statistic is computed for each individual study. A meta-analysis is then performed to combine individual study results with one of two options: a random-intercept logistic regression model or the inverse variance method. We demonstrated MetaGSCA in case studies investigating two human diseases and identified pathways highly relevant to each disease across studies. We further applied MetaGSCA in a pan-cancer analysis with hundreds of major cellular pathways in 11 cancer types. The results indicated that a majority of the pathways identified were dysregulated in the pan-cancer scenario, many of which have been previously reported in the cancer literature. Our analysis with randomly generated gene sets showed excellent specificity, indicating that the significant pathways/gene sets identified by MetaGSCA are unlikely false positives. MetaGSCA is a user-friendly tool implemented in both forms of a Web-based application and an R package "MetaGSCA". It enables comprehensive meta-analyses of gene set differential coexpression data, with an optional module of post hoc pathway crosstalk network analysis to identify and visualize pathways having similar coexpression profiles.
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Affiliation(s)
- Yan Guo
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Hui Yu
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Haocan Song
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Jiapeng He
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Olufunmilola Oyebamiji
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Huining Kang
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Jie Ping
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Scott Ness
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Vanderbilt Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Fei Ye
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- Vanderbilt Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
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31
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Chinopoulos C. From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity. Front Physiol 2020; 11:543564. [PMID: 33335484 PMCID: PMC7736077 DOI: 10.3389/fphys.2020.543564] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 11/02/2020] [Indexed: 12/14/2022] Open
Abstract
A metabolic hallmark of many cancers is the increase in glucose consumption coupled to excessive lactate production. Mindful that L-lactate originates only from pyruvate, the question arises as to how can this be sustained in those tissues where pyruvate kinase activity is reduced due to dimerization of PKM2 isoform or inhibited by oxidative/nitrosative stress, posttranslational modifications or mutations, all widely reported findings in the very same cells. Hereby 17 pathways connecting glucose to lactate bypassing pyruvate kinase are reviewed, some of which transit through the mitochondrial matrix. An additional 69 converging pathways leading to pyruvate and lactate, but not commencing from glucose, are also examined. The minor production of pyruvate and lactate by glutaminolysis is scrutinized separately. The present review aims to highlight the ways through which L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and underscore the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation.
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32
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Sun L, Zhu D, Beverborg LOG, Wang R, Dang Y, Ma M, Li W, Yu B. Synthesis and Antiproliferative Activities of
OSW
‐1 Analogues Bearing 2”‐
O
‐
p
‐Acylaminobenzoyl
Residues
†. CHINESE J CHEM 2020. [DOI: 10.1002/cjoc.202000110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Lijun Sun
- Department of Chemistry, University of Science and Technology of China 96 Jinzhai Road Hefei Anhui 230026 China
- State Key Laboratory of Bio‐organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345 Lingling Road Shanghai 200032 China
| | - Di Zhu
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai 200032 China
| | - Laura Olde Groote Beverborg
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai 200032 China
| | - Ruina Wang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai 200032 China
| | - Yongjun Dang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai 200032 China
| | - Mingming Ma
- Department of Chemistry, University of Science and Technology of China 96 Jinzhai Road Hefei Anhui 230026 China
| | - Wei Li
- Department of Medicinal Chemistry, China Pharmaceutical University 639 Longmian Avenue Nanjing Jiangsu 211198 China
| | - Biao Yu
- State Key Laboratory of Bio‐organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345 Lingling Road Shanghai 200032 China
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Rodríguez-Vázquez L, Martí J. Administration of 5-bromo-2'-deoxyuridine interferes with neuroblast proliferation and promotes apoptotic cell death in the rat cerebellar neuroepithelium. J Comp Neurol 2020; 529:1081-1096. [PMID: 32785933 DOI: 10.1002/cne.25005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/09/2020] [Accepted: 08/05/2020] [Indexed: 12/13/2022]
Abstract
The current study was conducted to assess whether a single administration of 5-bromo-2'-deoxyuridine (BrdU) interferes with cell proliferation and leads to the activation of apoptotic cellular events in the prenatal cerebellum. BrdU effects across a wide range of doses (25-300 μg/g b.w.) were analyzed using immunohistochemical and ultrastructural procedures. The pregnant rats were injected with BrdU at embryonic day 13, and their fetuses were sacrificed from 5 to 35 hr after exposure. The quantification of several parameters such as the density of mitotic figures, and BrdU and proliferating cell nuclear antigen (PCNA)-reactive cells showed that, in comparison with the saline injected rats, the administration of BrdU impairs the proliferative behavior of neuroepithelial cells. The above-mentioned parameters were significantly reduced in rats injected with 100 μg/g b.w. of BrdU. The reduction was more evident using 200 μg/g b.w. The most severe effects were found with 300 μg/g b.w. of BrdU. The present findings also revealed that high doses of BrdU lead to the activation of apoptotic cellular events as evidenced by both terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and immunohistochemistry for active caspase-3. In comparison with saline rats, many apoptotic cells were found in rats injected with 100 μg/g b.w. of BrdU. The number of dying cells increased with 200 μg/g b.w. The most important number of apoptotic cells were observed in animals injected with 300 μg/g b.w. of BrdU. Ultrastructural studies confirmed the presence of neuroblasts at different stages of apoptosis.
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Affiliation(s)
- Lucía Rodríguez-Vázquez
- Unidad de Citología e Histología, Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Facultad de Biociencias, Institut de Neurociències, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Joaquín Martí
- Unidad de Citología e Histología, Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Facultad de Biociencias, Institut de Neurociències, Universidad Autónoma de Barcelona, Barcelona, Spain
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Hu L, Liu J, Zhang W, Wang T, Zhang N, Lee YH, Lu H. FUNCTIONAL METABOLOMICS DECIPHER BIOCHEMICAL FUNCTIONS AND ASSOCIATED MECHANISMS UNDERLIE SMALL-MOLECULE METABOLISM. MASS SPECTROMETRY REVIEWS 2020; 39:417-433. [PMID: 31682024 DOI: 10.1002/mas.21611] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 06/10/2023]
Abstract
Metabolism is the collection of biochemical reactions enabled by chemically diverse metabolites, which facilitate different physiological processes to exchange substances and synthesize energy in diverse living organisms. Metabolomics has emerged as a cutting-edge method to qualify and quantify the metabolites in different biological matrixes, and it has the extraordinary capacity to interrogate the biological significance that underlies metabolic modification and modulation. Liquid chromatography combined with mass spectrometry (LC/MS), as a robust platform for metabolomics analysis, has increased in popularity over the past 10 years due to its excellent sensitivity, throughput, and versatility. However, metabolomics investigation currently provides us with only phenotype data without revealing the biochemical functions and associated mechanisms. This limitation indeed weakens the core value of metabolomics data in a broad spectrum of the life sciences. In recent years, the scientific community has actively explored the functional features of metabolomics and translated this cutting-edge approach to be used to solve key multifaceted questions, such as disease pathogenesis, the therapeutic discovery of drugs, nutritional issues, agricultural problems, environmental toxicology, and microbial evolution. Here, we are the first to briefly review the history and applicable progression of LC/MS-based metabolomics, with an emphasis on the applications of metabolic phenotyping. Furthermore, we specifically highlight the next era of LC/MS-based metabolomics to target functional metabolomes, through which we can answer phenotype-related questions to elucidate biochemical functions and associated mechanisms implicated in dysregulated metabolism. Finally, we propose many strategies to enhance the research capacity of functional metabolomics by enabling the combination of contemporary omics technologies and cutting-edge biochemical techniques. The main purpose of this review is to improve the understanding of LC/MS-based metabolomics, extending beyond the conventional metabolic phenotype toward biochemical functions and associated mechanisms, to enhance research capability and to enlarge the applicable scope of functional metabolomics in small-molecule metabolism in different living organisms.
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Affiliation(s)
- Longlong Hu
- Laboratory for Functional Metabolomics Science, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jingjing Liu
- Laboratory for Functional Metabolomics Science, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Wenhua Zhang
- Laboratory for Functional Metabolomics Science, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
- Department of Pharmacognosy, College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Tianyu Wang
- Laboratory for Functional Metabolomics Science, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ning Zhang
- Department of Pharmacognosy, College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
- Department of Pharmaceutical Analysis, College of Jiamusi, Heilongjiang University of Chinese Medicine, Harbin, 121000, China
| | - Yie Hou Lee
- Translational 'Omics and Biomarkers Group, KK Research Centre, KK Women's and Children's Hospital, Singapore, 229899, Singapore
- OBGYN-Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Haitao Lu
- Laboratory for Functional Metabolomics Science, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China
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35
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Mastrogamvraki N, Zaravinos A. Signatures of co-deregulated genes and their transcriptional regulators in colorectal cancer. NPJ Syst Biol Appl 2020; 6:23. [PMID: 32737302 PMCID: PMC7395738 DOI: 10.1038/s41540-020-00144-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
The deregulated genes in colorectal cancer (CRC) vary significantly across different studies. Thus, a systems biology approach is needed to identify the co-deregulated genes (co-DEGs), explore their molecular networks, and spot the major hub proteins within these networks. We reanalyzed 19 GEO gene expression profiles to identify and annotate CRC versus normal signatures, single-gene perturbation, and single-drug perturbation signatures. We identified the co-DEGs across different studies, their upstream regulating kinases and transcription factors (TFs). Connectivity Map was used to identify likely repurposing drugs against CRC within each group. The functional changes of the co-upregulated genes in the first category were mainly associated with negative regulation of transforming growth factor β production and glomerular epithelial cell differentiation; whereas the co-downregulated genes were enriched in cotranslational protein targeting to the membrane. We identified 17 hub proteins across the co-upregulated genes and 18 hub proteins across the co-downregulated genes, composed of well-known TFs (MYC, TCF3, PML) and kinases (CSNK2A1, CDK1/4, MAPK14), and validated most of them using GEPIA2 and HPA, but also through two signature gene lists composed of the co-up and co-downregulated genes. We further identified a list of repurposing drugs that can potentially target the co-DEGs in CRC, including camptothecin, neostigmine bromide, emetine, remoxipride, cephaeline, thioridazine, and omeprazole. Similar analyses were performed in the co-DEG signatures in single-gene or drug perturbation experiments in CRC. MYC, PML, CDKs, CSNK2A1, and MAPKs were common hub proteins among all studies. Overall, we identified the critical genes in CRC and we propose repurposing drugs that could be used against them.
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Affiliation(s)
- Natalia Mastrogamvraki
- Department of Life Sciences, School of Sciences, European University Cyprus, 1516, Nicosia, Cyprus
| | - Apostolos Zaravinos
- Department of Basic Medical Sciences, College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.
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Nandi S, Dey M. Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2. J Biol Chem 2020; 295:5390-5403. [PMID: 32144209 PMCID: PMC7170521 DOI: 10.1074/jbc.ra120.013030] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.
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Affiliation(s)
- Suparno Nandi
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242
| | - Mishtu Dey
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242.
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