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Zhou Y, Yu S, Zhu L, Wang Y, Duan C, Li D, Du J, Zhang J, Zhang J, Ma R, He J, Ren Y, Wang B. Molecular biomarkers for the prognosis of breast cancer: role of amino acid metabolism genes. J Physiol Biochem 2025:10.1007/s13105-025-01088-5. [PMID: 40493339 DOI: 10.1007/s13105-025-01088-5] [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: 08/12/2024] [Accepted: 04/29/2025] [Indexed: 06/12/2025]
Abstract
The development of precise molecular biomarkers for breast cancer prognosis holds immense potential to improve treatment outcomes. This study aimed to investigate the role of amino acid metabolism genes as predictive markers for breast cancer prognosis and their association with the immune-tumour microenvironment. By employing advanced machine learning algorithms and bioinformatics analysis techniques, the impact of amino acid metabolism-related genes (AAMRGs) on the immune status and overall survival of patients with breast cancer was examined. An AAMRG-based risk model was established to assess the prognostic significance. Validated risk models (AIMP2, IYD, and QARS1) accurately predicted patient outcomes [1 y: 0.87 (0.96-0.78); 3 y: 0.82 (0.87-0.76); 5 y: 0.80 (0.86-0.75)]. Furthermore, this study revealed evidence suggesting that QARS1 may influence breast cancer cell proliferation through methionine metabolism. This analysis provides valuable insights into the mechanisms of breast cancer, emphasizing the significance of AAMRGs as prognostic biomarkers and potential therapeutic targets for optimizing personalized treatment strategies.
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Affiliation(s)
- Yudong Zhou
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Shibo Yu
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lizhe Zhu
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yalong Wang
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Chenglong Duan
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Danni Li
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jinsui Du
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jiaqi Zhang
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jianing Zhang
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China
- School of Medicine, Shaan'xi Province, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ruichao Ma
- Beijing university of post and telecommunication, Beijing, 100876, China
| | - Jianjun He
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China.
| | - Yu Ren
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China.
| | - Bin Wang
- Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaan'xi Province, China.
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Vo VTA, Tran LN, Bui TT, Lee HW, Jeong Y. Etoposide-induced protein 2.4 homolog promotes argininosuccinate synthase 1 and cancer cell survival upon arginine deprivation. Cell Mol Biol Lett 2025; 30:52. [PMID: 40253325 PMCID: PMC12008907 DOI: 10.1186/s11658-025-00726-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 04/03/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND Arginine auxotrophy has been reported in a subset of cancers with inherently defective de novo arginine synthesis. However, the use of arginine deprivation therapy seems to be unequally effective, partially owing to the resistance acquired by cancer cells. Study of underlying factors involved in this response thus becomes of utmost importance. Meanwhile, the function of etoposide-induced 2.4 homolog (EI24) in cancer metabolism, and specifically in arginine metabolism, remains unknown. METHODS EI24 was overexpressed in cancer cells using a doxycycline-inducible system or adenovirus transduction, while siRNA was used to knockdown EI24. Amino acid(s) deprivation medium was exploited with a cell viability assay to check the reliance of cancer cell survival on arginine. Protein expression and activation were examined through western blot and co-immunoprecipitation blot. Furthermore, global and specific protein translation were assessed through the SUnSET assay and polysome fractionation analysis. Gene expression and arginine level were downloaded from public cancer datasets for in silico validation including gene set enrichment and survival analysis to objectively evaluate the association between EI24 and arginine metabolism. RESULTS EI24 promoted cancer survival under arginine starvation. Mechanistically, EI24 replenished translation of argininosuccinate synthase 1 (ASS1) by inducing the inactive S-nitrosylated form of phosphatase and tensin homolog (PTEN), leading to release of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) axis. This tumor-promoting action of EI24 could be found in multiple ASS1-deficient cancer cells regardless of p53 status. Furthermore, expression of EI24 was linked to enrichment of arginine metabolism pathway as well as poor survival of patients with cancer across various cancer types, suggesting its role in cancer resistance to arginine deprivation. CONCLUSIONS This study is the first to report the role of EI24 in promoting cancer survival via translational regulation of the metabolic enzyme ASS1, thus paving a route for further investigation into the link between EI24 and cancer metabolism.
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Affiliation(s)
- Vu T A Vo
- Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Organelle Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
| | - Le Nhat Tran
- Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Organelle Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
| | - Thu Thanh Bui
- Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
- Organelle Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Yangsik Jeong
- Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
- Organelle Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
- Institute of Mitochondrial Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
- ONCOin, Ltd., Startup cube #2 - 204, 1 Kangwondaehakgil, Chuncheon, Republic of Korea.
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Panda PK, Paschoalini Mafra AC, Bastos AC, Cao L, Serra Bonet M, Brashears CB, Chen EY, Benedict-Hamilton HM, Ehrhardt W, Bomalaski J, Dehner C, Rogers LC, Oyama T, Van Tine BA. BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis. Clin Cancer Res 2025; 31:1333-1345. [PMID: 39898973 PMCID: PMC11964295 DOI: 10.1158/1078-0432.ccr-24-2548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/26/2024] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
PURPOSE Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis. EXPERIMENTAL DESIGN The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled. RESULTS Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo. CONCLUSIONS The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.
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Affiliation(s)
- Prashanta Kumar Panda
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Ana Carolina Paschoalini Mafra
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Alliny C.S. Bastos
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Li Cao
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Maria Serra Bonet
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Caitlyn B. Brashears
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Ethan Yang Chen
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Heather M. Benedict-Hamilton
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - William Ehrhardt
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | | | - Carina Dehner
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Leonard C. Rogers
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Toshinao Oyama
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Brian A. Van Tine
- Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Siteman Cancer Center, St. Louis, Missouri
- Department of Pediatric Hematology/Oncology, St. Louis Children’s Hospital, St. Louis, Missouri
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Canè S, Geiger R, Bronte V. The roles of arginases and arginine in immunity. Nat Rev Immunol 2025; 25:266-284. [PMID: 39420221 DOI: 10.1038/s41577-024-01098-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 10/19/2024]
Abstract
Arginase activity and arginine metabolism in immune cells have important consequences for health and disease. Their dysregulation is commonly observed in cancer, autoimmune disorders and infectious diseases. Following the initial description of a role for arginase in the dysfunction of T cells mounting an antitumour response, numerous studies have broadened our understanding of the regulation and expression of arginases and their integration with other metabolic pathways. Here, we highlight the differences in arginase compartmentalization and storage between humans and rodents that should be taken into consideration when assessing the effects of arginase activity. We detail the roles of arginases, arginine and its metabolites in immune cells and their effects in the context of cancer, autoimmunity and infectious disease. Finally, we explore potential therapeutic strategies targeting arginases and arginine.
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Affiliation(s)
- Stefania Canè
- The Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Roger Geiger
- Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Oncology Research (IOR), Università della Svizzera italiana, Bellinzona, Switzerland
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Xia J, Liu W, Ni Y, Shahzad A, Cui K, Xu Z, Zhang J, Wei Z, Teng Z, Yang Z, Zhang Q. Advances in the impact of ASS1 dysregulation on metabolic reprogramming of tumor cells. Cell Signal 2025; 127:111593. [PMID: 39778698 DOI: 10.1016/j.cellsig.2025.111593] [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: 11/13/2024] [Revised: 12/29/2024] [Accepted: 01/04/2025] [Indexed: 01/11/2025]
Abstract
ASS1(argininosuccinate synthase 1) is a rate-limiting enzyme in the urea cycle, catalyzing the synthesis of argininosuccinate from citrulline and aspartate to ultimately produce arginine and support cellular metabolism. Increasing evidence suggests that ASS1 is commonly dysregulated in the tumor microenvironment, promoting tumor cell metastasis and infiltration. With a deeper understanding of tumor metabolic reprogramming in recent years, the impact of ASS1 dysregulation on abnormal tumor metabolism has attracted growing interest among researchers. In tumors with lacked or downregulated expression of ASS1, tumor cells become 'addicted' to exogenous arginine. Several strategies for arginine deprivation have been developed and entered clinical trials for treating such tumors. Therefore, we focus on elucidating the commonalities and characteristics of ASS1 dysregulation in tumors, as well as its implications for diagnosis, treatment, and prognosis. The mechanisms by which ASS1 gene dysregulation leads to metabolic abnormalities in tumor cells vary across different types of tumors. Extensive experimental studies have demonstrated that overexpression or low expression of ASS1 exhibits varying effects-either inhibitory or stimulatory proliferation-on tumor cells across different types. Restoring its expression can inhibit proliferation in some tumors lacking or downregulating ASS1 but can promote metastasis and infiltration in others (e.g., resistance to arginine deprivation therapy). Additionally, the expression level of ASS1 dynamically changes during tumorigenesis and progression. Finally, this review discusses the diagnostic, therapeutic, and prognostic value of ASS1 in future clinical practice.
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Affiliation(s)
- Jiaojiao Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Wenjing Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Yueli Ni
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Asif Shahzad
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Kun Cui
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Zhe Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China; Qujing Medical College, Qujing 655011, Yunnan Province, China
| | - Jinshan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China
| | - Zhenyan Wei
- Yunnan Center for Disease Control and Prevention, Kunming 650022, China
| | - Zhuoran Teng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China.
| | - Zhe Yang
- Departments of Pathology, The First Affiliated Hospital of Kunming Medical University, Yunnan, Kunming 650032, PR China.
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Yunnan, Kunming 650500, PR China.
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Avram L, Crișan D, Moldovan RC, Bogos LG, Iuga CA, Andraș D, Crișan S, Bodolea C, Nemeş A, Donca V. Metabolomic Exploration of Colorectal Cancer Through Amino Acids and Acylcarnitines Profiling of Serum Samples. Cancers (Basel) 2025; 17:427. [PMID: 39941796 PMCID: PMC11816151 DOI: 10.3390/cancers17030427] [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: 12/17/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES Colorectal cancer (CRC) represents one of the most prevalent forms of cancer, with high mortality rates. The aim of this study was to observe and understand the metabolic changes in CRC through targeted metabolomics. METHODS Samples collected from 58 CRC patients and 35 healthy individuals have been analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), targeting two classes of metabolites: amino acids and acylcarnitines. RESULTS Statistical analysis revealed 26 significantly modified (p-value < 0.01; |FC| > 1.2) metabolites in CRC patients compared to the control group and 22 between colon cancer and control, whereas 8 metabolites differed only significantly between rectal cancer and healthy patients. Some of these significantly modified metabolites characterize cancer-specific adaptations, such as increased energy demand, increased tumor invasiveness, capabilities to promote amino acid synthesis, and tumor resistance against acute immune response. Moreover, receiver operator characteristic (ROC) analysis revealed that a set of two acylcarnitines (C6DC and C4-OH) can differentiate between CRC patients and healthy individuals with a high degree of confidence (AUC 0.837). CONCLUSIONS By implementing a metabolomics approach targeting amino acids and acylcarnitines, several metabolic alterations induced by CRC have been highlighted. Even though these modifications are not specific enough to act as disease markers, they might prove useful for evaluating patient status.
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Affiliation(s)
- Lucreția Avram
- Geriatrics—Gerontology, Department 5—Medical Specialties, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (L.A.); (V.D.)
| | - Dana Crișan
- Department of Internal Medicine, 5th Medical Clinic, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (D.C.); (S.C.)
| | - Radu-Cristian Moldovan
- Department of Personalized Medicine and Rare Diseases, Institute of Biomedical Research—MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (L.-G.B.); (C.-A.I.)
| | - Luisa-Gabriela Bogos
- Department of Personalized Medicine and Rare Diseases, Institute of Biomedical Research—MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (L.-G.B.); (C.-A.I.)
| | - Cristina-Adela Iuga
- Department of Personalized Medicine and Rare Diseases, Institute of Biomedical Research—MedFuture, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (L.-G.B.); (C.-A.I.)
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - David Andraș
- 1st Surgical Clinic, Department of General Surgery, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj Napoca, Romania;
| | - Sorin Crișan
- Department of Internal Medicine, 5th Medical Clinic, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (D.C.); (S.C.)
| | - Constantin Bodolea
- Intensive Care Unit Department, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.B.); (A.N.)
| | - Andrada Nemeş
- Intensive Care Unit Department, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.B.); (A.N.)
| | - Valer Donca
- Geriatrics—Gerontology, Department 5—Medical Specialties, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania; (L.A.); (V.D.)
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Li M, Zhang Y, Zhang T, Miao M. Enhanced thermostability and catalytic activity for arginine deiminase from Enterobacter faecalis SK32.001 via combinatorial mutagenesis. Int J Biol Macromol 2025; 284:138004. [PMID: 39586434 DOI: 10.1016/j.ijbiomac.2024.138004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/14/2024] [Accepted: 11/22/2024] [Indexed: 11/27/2024]
Abstract
Arginine deiminase (ADI) exhibits potential for clinical and industrial applications, yet its low thermostability and catalytic efficiency under physiological conditions limit its utility. In this work, the ADI of Enterococcus faecalis SK32.001 was rationally designed. A total of 120 combinatorial mutants, ranging from two-point to six-point mutations, were constructed by sequentially stacking single-point positive mutants (F44W, N163P, E220L, N318E, A336G, T340I). Among them, the mutants S604, S700, S601, and S606 exhibited higher Tm values, while the mutants S605, S547, S602, S607, S517, and S557 demonstrated enhanced enzymatic activity. Notably, the five-point mutant S547 (F44W/N163P/E220I/A336G/T340I) exhibited remarkable pH tolerance (pH 4.5-9.5, with over 80 % residual enzyme activity). Its specific enzyme activity reached 131.60 U/mg, which was 2-fold higher than that of wild enzyme. The Tm value of this enzyme increases to 64.04 °C, 11.62 °C higher than that of the wild-type enzyme. The structure predicted by AlphaFold 2 revealed that the increased rigidity, formation of new hydrogen bonds, and an increase in hydrophobic residues may account for the enhanced enzyme activity and thermostability. This research demonstrates that rational design strategies can effectively optimize enzyme properties, providing insights for the development of microbial enzymes with industrial relevance.
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Affiliation(s)
- Mengli Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Yijing Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Tao Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Ming Miao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; International Joint Laboratory on Food Science and Safety, Jiangnan University, Wuxi, Jiangsu 214122, China
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Kumari S, Gupta S, Jamil A, Tabatabaei D, Karakashev S. Exploring Metabolic Approaches for Epithelial Ovarian Cancer Therapy. J Cell Physiol 2025; 240:e31495. [PMID: 39676338 DOI: 10.1002/jcp.31495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 10/21/2024] [Accepted: 11/18/2024] [Indexed: 12/17/2024]
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate among malignant tumors of the female reproductive system and the lowest survival rate. This poor prognosis is due to the aggressive nature of EOC, its late-stage diagnosis, and the tumor's ability to adapt to stressors through metabolic reprogramming. EOC cells sustain their rapid proliferation by altering the uptake, utilization, and regulation of carbohydrates, lipids, and amino acids. These metabolic changes support tumor growth and contribute to metastasis, chemotherapy resistance, and immune evasion. Targeting these metabolic vulnerabilities has shown promise in preclinical studies, with some therapies advancing to clinical trials. However, challenges remain due to tumor heterogeneity, adaptive resistance mechanisms, and the influence of the tumor microenvironment. This review provides a comprehensive summary of metabolic targets for EOC treatment and offers an overview of the current landscape of clinical trials focusing on ovarian cancer metabolism. Future efforts should prioritize combination therapies that integrate metabolic inhibitors with immunotherapies or chemotherapy. Advances in precision medicine and multi-omics approaches will be crucial for identifying patient-specific metabolic dependencies and improving outcomes. By addressing these challenges, metabolism-based therapies can significantly transform the treatment of this devastating disease.
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Affiliation(s)
- Sangeeta Kumari
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Shraddha Gupta
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Aisha Jamil
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Deyana Tabatabaei
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA
| | - Sergey Karakashev
- Fels Cancer Institute for Personalized Medicine and Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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Li D, Zhang Z, Wang L. Emerging role of tumor microenvironmental nutrients and metabolic molecules in ferroptosis: Mechanisms and clinical implications. Biomed Pharmacother 2024; 179:117406. [PMID: 39255738 DOI: 10.1016/j.biopha.2024.117406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 08/22/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024] Open
Abstract
In recent years, ferroptosis has gradually attracted increasing attention because of its important role in tumors. Ferroptosis resistance is an important cause of tumor metastasis, recurrence and drug resistance. Exploring the initiating factors and specific mechanisms of ferroptosis has become a key strategy to block tumor progression and improve drug sensitivity. As the external space in direct contact with tumor cells, the tumor microenvironment has a great impact on the biological function of tumor cells. The relationships between abnormal environmental characteristics (hypoxia, lactic acid accumulation, etc.) in the microenvironment and ferroptosis of tumor cells has not been fully characterized. This review focuses on the characteristics of the tumor microenvironment and summarizes the mechanisms of ferroptosis under different environmental factors, aiming to provide new insights for subsequent targeted therapy. Moreover, considering the presence of anticancer drugs in the microenvironment, we further summarize the mechanisms of ferroptosis to provide new strategies for the sensitization of tumor cells to drugs.
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Affiliation(s)
- Dongyu Li
- Department of VIP In-Patient Ward, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zhe Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Lei Wang
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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10
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Zhang Y, Zhang T, Li M, Miao M. Rational design to improve the catalytic efficiency and stability of arginine deiminase. Int J Biol Macromol 2024; 269:132083. [PMID: 38705327 DOI: 10.1016/j.ijbiomac.2024.132083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/10/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Arginine deiminase (ADI) has garnered significant interest because of its ability to objectively eradicate cancer cells and produce L-citrulline. To meet the production demands, this study focused on enhancing the enzyme activity and thermal stability of ADI. In this study, 24 ADI mutants were obtained through computer aid site-specific mutation in the ADI of Enterobacter faecalis. Notably, the specific enzyme activities of F44W, N163P, E220I, E220L, N318E, A336G, T340I, and N382F increased, reaching 1.33-2.53 times that of the original enzyme. This study confirmed that site-specific mutations are critical for optimizing enzyme function. Additionally, the F44W, N163P, E220I, T340I, and A336G mutants demonstrated good thermal stability. The optimal pH for mutant F44W increased to 8, whereas mutants E220I, I244V, A336G, T340I, and N328F maintained an optimal pH of 7.5. Conversely, the M109L, N163P, E220L, I244L, and N318E mutants shad an optimal pH of 7. This study revealed that mutant enzymes with increased activity were more likely to contain mutation sites situated near the four loops associated with catalytic residues, whereas mutations at the dimer junction sites had a higher tendency to enhance enzyme stability. These findings contribute to the development of ADI industrial applications and its modifications.
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Affiliation(s)
- Yijing Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Tao Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | - Mengli Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China
| | - Ming Miao
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu 214122, China; International Joint Laboratory on Food Science and Safety, Jiangnan University, Wuxi, Jiangsu 214122, China
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11
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Chang Y, Dai T, Song G, Wang S, Pei H, Shen G, Feng J. Metabolomic analysis reveals the biological characteristics of giant congenital melanocytic nevi. J Pharm Biomed Anal 2024; 242:116060. [PMID: 38382316 DOI: 10.1016/j.jpba.2024.116060] [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: 01/12/2024] [Revised: 02/16/2024] [Accepted: 02/16/2024] [Indexed: 02/23/2024]
Abstract
Giant congenital melanocytic nevi (GCMN) is a congenital cutaneous developmental deformity tumor that usually occurs at birth or in the first few weeks after birth, but its pathogenesis is still unclear. In this study, nuclear magnetic resonance-based metabolomics strategy was employed to evaluate the metabolic variations in serum and urine of the GCMN patients in order to understand its underlying biochemical mechanism and provide a potential intervention idea. Twenty-nine metabolites were observed to change significantly in serum and urine metabolomes, which are mainly involved in a variety of metabolic pathways including glyoxylate and dicarboxylate metabolism, TCA cycle and metabolisms of amino acids. The substantial cores of all the disturbed metabolic pathways are related to amino acid metabolism and carbohydrate metabolism and regulate the physiological state of the GCMN patients. Our results provide the physiological basis and physiological responses of GCMN and will be helpful for better understanding the molecular mechanisms of GCMN in future research.
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Affiliation(s)
- Yajie Chang
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
| | - Tao Dai
- Department of Wound Reconstructive Surgery, Tongji Hospital of Tongji University, Shanghai 200065, China.
| | - Ge Song
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China; Department of Plastic Surgery, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, China
| | - Sanxi Wang
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
| | - Huile Pei
- Department of Dermatology, Second Affiliated Hospital Henan University of Science and Technology, Luoyang 471003, China
| | - Guiping Shen
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China.
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China
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12
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Liang C, Lin L, Hu J, Ma Y, Li Y, Sun Z. Comprehensive pulmonary metabolic responses to silica nanoparticles exposure in Fisher 344 rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 275:116256. [PMID: 38554605 DOI: 10.1016/j.ecoenv.2024.116256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 03/09/2024] [Accepted: 03/21/2024] [Indexed: 04/02/2024]
Abstract
Silica nanoparticles (SiNPs) could induce adverse pulmonary effects, but the mechanism was not clear enough. Metabolomics is a sensitive and high-throughput approach that could investigate the intrinsic causes of adverse health effects caused by SiNPs. The current investigation represented the first in vivo metabolomics study examining the chronic pulmonary toxicity of SiNPs at a low dosage, mimicking real human exposure situation. The recovery process after the cessation of exposure was also taken into consideration. Fisher 344 rats were treated with either saline or SiNPs for 6 months. Half of the animals in each group received an additional six-month period for recovery. The findings indicated that chronic low-level exposure to SiNPs resulted in notable alterations in pulmonary metabolism of amino acids, lipids, carbohydrates, and nucleotides. SiNPs exerted an impact on various metabolites and metabolic pathways which are linked to oxidative stress, inflammation and tumorigenesis. These included but were not limited to L-carnitine, spermidine, taurine, xanthine, and glutathione metabolism. The metabolic alterations caused by SiNPs exhibited a degree of reversibility. However, the interference of SiNPs on two metabolic pathways related to tumorigenesis was observed to persist after a recovery period. The two metabolic pathways are glycerophospholipid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis. This study elucidated the metabolic alterations induced by chronic low-level exposure to SiNPs and presented novel evidence of the chronic pulmonary toxicity and carcinogenicity of SiNPs, from a metabolomic perspective.
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Affiliation(s)
- Chen Liang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Lisen Lin
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Junjie Hu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Yuexiao Ma
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, PR China.
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13
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Chew HY, Cvetkovic G, Tepic S, Wells JW. Arginase-induced cell death pathways and metabolic changes in cancer cells are not altered by insulin. Sci Rep 2024; 14:4112. [PMID: 38374190 PMCID: PMC10876525 DOI: 10.1038/s41598-024-54520-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/13/2024] [Indexed: 02/21/2024] Open
Abstract
Arginine, a semi-essential amino acid, is critical for cell growth. Typically, de novo synthesis of arginine is sufficient to support cellular processes, however, it becomes vital for cancer cells that are unable to synthesise arginine due to enzyme deficiencies. Targeting this need, arginine depletion with enzymes such as arginase (ARG) has emerged as a potential cancer therapeutic strategy. Studies have proposed using high dose insulin to induce a state of hypoaminoacidaemia in the body, thereby further reducing circulating arginine levels. However, the mitogenic and metabolic properties of insulin could potentially counteract the therapeutic effects of ARG. Our study examined the combined impact of insulin and ARG on breast, lung, and ovarian cell lines, focusing on cell proliferation, metabolism, apoptosis, and autophagy. Our results showed that the influence of insulin on ARG uptake varied between cell lines but failed to promote the proliferation of ARG-treated cells or aid recovery post-ARG treatment. Moreover, insulin was largely ineffective in altering ARG-induced metabolic changes and did not prevent apoptosis. In vitro, at least, these findings imply that insulin does not offer a growth or survival benefit to cancer cells being treated with ARG.
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Affiliation(s)
- Hui Yi Chew
- Faculty of Medicine, Frazer Institute, The University of Queensland, 37 Kent Street, Brisbane, QLD, 4102, Australia
| | | | | | - James W Wells
- Faculty of Medicine, Frazer Institute, The University of Queensland, 37 Kent Street, Brisbane, QLD, 4102, Australia.
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14
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Shirley CA, Chhabra G, Amiri D, Chang H, Ahmad N. Immune escape and metastasis mechanisms in melanoma: breaking down the dichotomy. Front Immunol 2024; 15:1336023. [PMID: 38426087 PMCID: PMC10902921 DOI: 10.3389/fimmu.2024.1336023] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
Melanoma is one of the most lethal neoplasms of the skin. Despite the revolutionary introduction of immune checkpoint inhibitors, metastatic spread, and recurrence remain critical problems in resistant cases. Melanoma employs a multitude of mechanisms to subvert the immune system and successfully metastasize to distant organs. Concerningly, recent research also shows that tumor cells can disseminate early during melanoma progression and enter dormant states, eventually leading to metastases at a future time. Immune escape and metastasis have previously been viewed as separate phenomena; however, accumulating evidence is breaking down this dichotomy. Recent research into the progressive mechanisms of melanoma provides evidence that dedifferentiation similar to classical epithelial to mesenchymal transition (EMT), genes involved in neural crest stem cell maintenance, and hypoxia/acidosis, are important factors simultaneously involved in immune escape and metastasis. The likeness between EMT and early dissemination, and differences, also become apparent in these contexts. Detailed knowledge of the mechanisms behind "dual drivers" simultaneously promoting metastatically inclined and immunosuppressive environments can yield novel strategies effective in disabling multiple facets of melanoma progression. Furthermore, understanding progression through these drivers may provide insight towards novel treatments capable of preventing recurrence arising from dormant dissemination or improving immunotherapy outcomes.
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Affiliation(s)
- Carl A. Shirley
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Gagan Chhabra
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Deeba Amiri
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
| | - Hao Chang
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
- William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, WI, United States
- William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
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15
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Coleman M, Mascialino SJ, Panjwani A, Edwards E, Sukhatme VV, Gavegnano C, Sukhatme VP. Readily available drugs and other interventions to potentially improve the efficacy of immune checkpoint blockade in cancer. Front Immunol 2024; 14:1281744. [PMID: 38299150 PMCID: PMC10827885 DOI: 10.3389/fimmu.2023.1281744] [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: 08/23/2023] [Accepted: 12/29/2023] [Indexed: 02/02/2024] Open
Abstract
To improve the efficacy of immune checkpoint inhibitors (ICIs) for cancer treatment, various strategies, including combination therapies with repurposed drugs, are being explored. Several readily available interventions with potential to enhance programmed death 1 (PD-1) blockade have been identified. However, these interventions often remain overlooked due to the lack of financial incentives for their development, making them financial orphans. This review summarizes current knowledge regarding off-label drugs, supplements, and other readily available interventions that could improve the efficacy of PD-1 blockade. The summary of each intervention includes the proposed mechanism of action for combination with checkpoint inhibitors and data from animal and human studies. Additionally, we include summaries of common interventions to be avoided by patients on PD-1 blockade. Finally, we present approaches for conducting further studies in patients, with the aim of expediting the clinical development of these interventions. We strive to increase awareness of readily available combination therapies that may advance cancer immunotherapy and help patients today.
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Affiliation(s)
- Merissa Coleman
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
- Center for the Study of Human Health, Emory University, Atlanta, GA, United States
| | - Sophia J. Mascialino
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
- Center for the Study of Human Health, Emory University, Atlanta, GA, United States
| | - Anusha Panjwani
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
- Center for the Study of Human Health, Emory University, Atlanta, GA, United States
| | - Emily Edwards
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
- Center for the Study of Human Health, Emory University, Atlanta, GA, United States
- College of Pharmacy, University of Florida, Gainesville, FL, United States
| | - Vidula V. Sukhatme
- Morningside Center for Innovative & Affordable Medicine, Emory University, Atlanta, GA, United States
- GlobalCures, Inc, Newton, MA, United States
- Rollins School of Public Health, Emory University, Atlanta, GA, United States
| | - Christina Gavegnano
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
- Center for the Study of Human Health, Emory University, Atlanta, GA, United States
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, United States
- Atlanta Veterans Affairs Medical Center, Decatur, GA, United States
- Center for Bioethics, Harvard Medical School, Boston, MA, United States
- Department of Medicine, Emory University, Atlanta, GA, United States
| | - Vikas P. Sukhatme
- Morningside Center for Innovative & Affordable Medicine, Emory University, Atlanta, GA, United States
- GlobalCures, Inc, Newton, MA, United States
- Department of Medicine, Emory University, Atlanta, GA, United States
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, United States
- Winship Cancer Institute, Emory University, Atlanta, GA, United States
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16
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Cunningham A, Oudejans LL, Geugien M, Pereira-Martins DA, Wierenga ATJ, Erdem A, Sternadt D, Huls G, Schuringa JJ. The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia. Blood Adv 2024; 8:56-69. [PMID: 37906522 PMCID: PMC10784682 DOI: 10.1182/bloodadvances.2023010786] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/20/2023] [Accepted: 10/21/2023] [Indexed: 11/02/2023] Open
Abstract
ABSTRACT Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.
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Affiliation(s)
- Alan Cunningham
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lieve L. Oudejans
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marjan Geugien
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Diego Antonio Pereira-Martins
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Albertus T. J. Wierenga
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ayşegül Erdem
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Dominique Sternadt
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerwin Huls
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan Jacob Schuringa
- Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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17
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Jimenez J, Dubey P, Carter B, Koomen JM, Markowitz J. A metabolic perspective on nitric oxide function in melanoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189038. [PMID: 38061664 PMCID: PMC11380350 DOI: 10.1016/j.bbcan.2023.189038] [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: 07/19/2023] [Revised: 10/17/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023]
Abstract
Nitric oxide (NO) generated from nitric oxide synthase (NOS) exerts a dichotomous effect in melanoma, suppressing or promoting tumor progression. This dichotomy is thought to depend on the intracellular NO concentration and the cell type in which it is generated. Due to its central role in the metabolism of multiple critical constituents involved in signaling and stress, it is crucial to explore NO's contribution to the metabolic dysfunction of melanoma. This review will discuss many known metabolites linked to NO production in melanoma. We discuss the synthesis of these metabolites, their role in biochemical pathways, and how they alter the biological processes observed in the melanoma tumor microenvironment. The metabolic pathways altered by NO and the corresponding metabolites reinforce its dual role in melanoma and support investigating this effect for potential avenues of therapeutic intervention.
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Affiliation(s)
- John Jimenez
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida Morsani School of Medicine, Tampa, FL 33612, USA
| | - Parul Dubey
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Bethany Carter
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Flow Cytometry Core Facility, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - John M Koomen
- Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida Morsani School of Medicine, Tampa, FL 33612, USA.
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18
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Xing Z, Jiang X, Wu Y, Yu Z. Targeted Mevalonate Pathway and Autophagy in Antitumor Immunotherapy. Curr Cancer Drug Targets 2024; 24:890-909. [PMID: 38275055 DOI: 10.2174/0115680096273730231206054104] [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: 08/17/2023] [Revised: 09/30/2023] [Accepted: 10/11/2023] [Indexed: 01/27/2024]
Abstract
Tumors of the digestive system are currently one of the leading causes of cancer-related death worldwide. Despite considerable progress in tumor immunotherapy, the prognosis for most patients remains poor. In the tumor microenvironment (TME), tumor cells attain immune escape through immune editing and acquire immune tolerance. The mevalonate pathway and autophagy play important roles in cancer biology, antitumor immunity, and regulation of the TME. In addition, there is metabolic crosstalk between the two pathways. However, their role in promoting immune tolerance in digestive system tumors has not previously been summarized. Therefore, this review focuses on the cancer biology of the mevalonate pathway and autophagy, the regulation of the TME, metabolic crosstalk between the pathways, and the evaluation of their efficacy as targeted inhibitors in clinical tumor immunotherapy.
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Affiliation(s)
- Zongrui Xing
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
| | - Xiangyan Jiang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Yuxia Wu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Zeyuan Yu
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, Gansu, China
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19
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Zeb F, Mehreen A, Naqeeb H, Ullah M, Waleed A, Awan UA, Haider A, Naeem M. Nutrition and Dietary Intervention in Cancer: Gaps, Challenges, and Future Perspectives. Cancer Treat Res 2024; 191:281-307. [PMID: 39133412 DOI: 10.1007/978-3-031-55622-7_11] [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] [Indexed: 08/13/2024]
Abstract
The term "cancer" refers to the state in which cells in the body develop mutations and lose control over their replication. Malignant cancerous cells invade in various other tissue sites of the body. Chemotherapy, radiation, and surgery are the first-line modalities for the majority of solid cancers. These treatments work by mitigating the DNA damage of cancerous cells, but they can also cause harm to healthy cells. These side effects might be immediate or delayed, and they can cause a high rate of morbidity and mortality. Dietary interventions have a profound impact on whole-body metabolism, including immunometabolism and oncometabolism which have been shown to reduce cancer growth, progression, and metastasis in many different solid tumor models with promising outcomes in early phase clinical studies. Dietary interventions can improve oncologic or quality-of-life outcomes for patients that are undergoing chemotherapy or radiotherapy. In this chapter, we will focus on the impact of nutritional deficiencies, several dietary interventions and their proposed mechanisms which are used as a novel therapy in controlling and managing cancers.
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Affiliation(s)
- Falak Zeb
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Aqsa Mehreen
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Huma Naqeeb
- Department of Clinical Nutrition, Shaukat Khanum Memorial Cancer Hospital, and Research Center, Peshawar, Pakistan
| | - Muneeb Ullah
- College of Pharmacy, Pusan National University, Busan, South Korea
| | - Afraa Waleed
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Uzma Azeem Awan
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Adnan Haider
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Muhammad Naeem
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan.
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20
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Youssef R, Maniar R, Khan J, Mesa H. Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response. Curr Issues Mol Biol 2023; 45:9753-9767. [PMID: 38132455 PMCID: PMC10742411 DOI: 10.3390/cimb45120609] [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: 10/31/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/23/2023] Open
Abstract
Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.
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Affiliation(s)
- Reem Youssef
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rohan Maniar
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jaffar Khan
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hector Mesa
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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21
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Xu F, Jiang HL, Feng WW, Fu C, Zhou JC. Characteristics of amino acid metabolism in colorectal cancer. World J Clin Cases 2023; 11:6318-6326. [PMID: 37900242 PMCID: PMC10601002 DOI: 10.12998/wjcc.v11.i27.6318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/16/2023] [Accepted: 08/18/2023] [Indexed: 09/20/2023] Open
Abstract
In recent years, metabolomics research has become a hot spot in the screening and treatment of cancer. It is a popular technique for the quantitative characterization of small molecular compounds in biological cells, tissues, organs or organisms. Further study of the tumor revealed that amino acid changes may occur early in the tumor. The rapid growth and metabolism required for survival result in tumors exhibiting an increased demand for amino acids. An abundant supply of amino acids is important for cancer to maintain its proliferative driving force. Changes in amino acid metabolism can be used to screen malignant tumors and improve therapeutic outcomes. Therefore, it is particularly important to study the characteristics of amino acid metabolism in colorectal cancer. This article reviews several specific amino acid metabolism characteristics in colorectal cancer.
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Affiliation(s)
- Fen Xu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Dalian 116000, Liaoning Province, China
| | - Hong-Liang Jiang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Dalian 116000, Liaoning Province, China
| | - Wei-Wei Feng
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Dalian 116000, Liaoning Province, China
| | - Chen Fu
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Dalian 116000, Liaoning Province, China
| | - Jiang-Chang Zhou
- Department of Gastroenterology, Xinhua Hospital Affiliated to Dalian University, Dalian 116000, Liaoning Province, China
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22
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Rogers LC, Kremer JC, Brashears CB, Lin Z, Hu Z, Bastos AC, Baker A, Fettig N, Zhou D, Shoghi KI, Dehner CA, Chrisinger JS, Bomalaski JS, Garcia BA, Oyama T, White EP, Van Tine BA. Discovery and Targeting of a Noncanonical Mechanism of Sarcoma Resistance to ADI-PEG20 Mediated by the Microenvironment. Clin Cancer Res 2023; 29:3189-3202. [PMID: 37339179 PMCID: PMC10425734 DOI: 10.1158/1078-0432.ccr-22-2642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 04/11/2023] [Accepted: 06/15/2023] [Indexed: 06/22/2023]
Abstract
PURPOSE Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20. EXPERIMENTAL DESIGN Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo. RESULTS Conditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Coculture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo. CONCLUSIONS Noncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes.
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Affiliation(s)
- Leonard C. Rogers
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Jeff C. Kremer
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Caitlyn B. Brashears
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Zongtao Lin
- Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri
| | - Zhixian Hu
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
| | - Alliny C.S. Bastos
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Adriana Baker
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Nicole Fettig
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Dong Zhou
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - Kooresh I. Shoghi
- Department of Radiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri
| | - Carina A. Dehner
- Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | - John S.A. Chrisinger
- Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri
| | | | - Benjamin A. Garcia
- Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri
| | - Toshinao Oyama
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Eileen P. White
- Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
- Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey
| | - Brian A. Van Tine
- Division of Medical Oncology, Washington University in St. Louis, St. Louis, Missouri
- Division of Pediatric Hematology/Oncology, St. Louis Children's Hospital, St. Louis, Missouri
- Siteman Cancer Center, St. Louis, Missouri
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23
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Mahé M, Rios-Fuller TJ, Karolin A, Schneider RJ. Genetics of enzymatic dysfunctions in metabolic disorders and cancer. Front Oncol 2023; 13:1230934. [PMID: 37601653 PMCID: PMC10433910 DOI: 10.3389/fonc.2023.1230934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.
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Affiliation(s)
| | | | | | - Robert J. Schneider
- Department of Microbiology, Grossman NYU School of Medicine, New York, NY, United States
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24
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Chu YD, Lai MW, Yeh CT. Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment. Int J Mol Sci 2023; 24:10668. [PMID: 37445845 DOI: 10.3390/ijms241310668] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/19/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis-all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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25
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Dryja P, Curtsinger HD, Bartee MY, Bartee E. Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus. J Immunother Cancer 2023; 11:e006388. [PMID: 37270180 PMCID: PMC10254609 DOI: 10.1136/jitc-2022-006388] [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] [Accepted: 05/12/2023] [Indexed: 06/05/2023] Open
Abstract
BACKGROUND Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined. METHODS To address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1-/- tumors. RESULTS Our results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1-/- cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs. CONCLUSIONS These results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors.
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Affiliation(s)
- Parker Dryja
- Program in Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Heather D Curtsinger
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Mee Y Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Eric Bartee
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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26
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Thakker DP, Narayanan R. Arginine deiminase produced by lactic acid bacteria as a potent anti-cancer drug. Med Oncol 2023; 40:175. [PMID: 37171497 DOI: 10.1007/s12032-023-02043-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 04/30/2023] [Indexed: 05/13/2023]
Abstract
Bacterial-based cancer immunotherapy has recently gained widespread attention due to its exceptional mechanism of rich pathogen-associated molecular patterns in anti-cancer immune responses. Contrary to conventional cancer therapies such as surgery, chemotherapy, radiation and phototherapy, bacteria-based cancer immunotherapy has the unique ability to suppress cancer by selectively accumulating and growing in tumours. In the view of this, several bacterial strains are being used for the treatment of cancer. Of which, lactic acid bacteria are a powerful, albeit still inadequately understood bacteria that possess a wide source of bioactive chemicals. Lactic acid bacteria metabolites, such as bacteriocins, short-chain fatty acids, exopolysaccharides show antitumour property. Amino acid pathways, which have lately been focussed as a new strategy to cancer therapy, are key element of the adaptability and dysregulation of metabolic pathways identified in proliferation of tumour cells. Arginine metabolism, in particular, has been shown to be critical for cancer therapy. As a result, better understanding of arginine metabolism in LAB and cancer cells could lead to new cancer therapeutic targets. This review will outline current advances in the interaction of arginine metabolism with cancer therapy and propose an arginine deiminase expression system to combat cancer more effectively.
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Affiliation(s)
- Darshali P Thakker
- Department of Genetic Engineering, College of Engineering & Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603203, Tamil Nadu, India
| | - Rajnish Narayanan
- Department of Genetic Engineering, College of Engineering & Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603203, Tamil Nadu, India.
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27
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Anakha J, Prasad YR, Sharma N, Pande AH. Human arginase I: a potential broad-spectrum anti-cancer agent. 3 Biotech 2023; 13:159. [PMID: 37152001 PMCID: PMC10156892 DOI: 10.1007/s13205-023-03590-3] [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: 11/19/2022] [Accepted: 04/23/2023] [Indexed: 05/09/2023] Open
Abstract
With high rates of morbidity and mortality, cancer continues to pose a serious threat to public health on a global scale. Considering the discrepancies in metabolism between cancer and normal cells, metabolism-based anti-cancer biopharmaceuticals are gaining importance. Normal cells can synthesize arginine, but they can also take up extracellular arginine, making it a semi-essential amino acid. Arginine auxotrophy occurs when a cancer cell has abnormalities in the enzymes involved in arginine metabolism and relies primarily on extracellular arginine to support its biological functions. Taking advantage of arginine auxotrophy in cancer cells, arginine deprivation, which can be induced by introducing recombinant human arginase I (rhArg I), is being developed as a broad-spectrum anti-cancer therapy. This has led to the development of various rhArg I variants, which have shown remarkable anti-cancer activity. This article discusses the importance of arginine auxotrophy in cancer and different arginine-hydrolyzing enzymes that are in various stages of clinical development and reviews the need for a novel rhArg I that mitigates the limitations of the existing therapies. Further, we have also analyzed the necessity as well as the significance of using rhArg I to treat various arginine-auxotrophic cancers while considering the importance of their genetic profiles, particularly urea cycle enzymes.
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Affiliation(s)
- J. Anakha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, 160062 Punjab India
| | - Yenisetti Rajendra Prasad
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, 160062 Punjab India
| | - Nisha Sharma
- Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, 160062 Punjab India
| | - Abhay H. Pande
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, 160062 Punjab India
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28
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Murali R, Balasubramaniam V, Srinivas S, Sundaram S, Venkatraman G, Warrier S, Dharmarajan A, Gandhirajan RK. Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence. Metabolites 2023; 13:metabo13040560. [PMID: 37110218 PMCID: PMC10141515 DOI: 10.3390/metabo13040560] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Ovarian cancers are tumors that originate from the different cells of the ovary and account for almost 4% of all the cancers in women globally. More than 30 types of tumors have been identified based on the cellular origins. Epithelial ovarian cancer (EOC) is the most common and lethal type of ovarian cancer which can be further divided into high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous carcinoma. Ovarian carcinogenesis has been long attributed to endometriosis which is a chronic inflammation of the reproductive tract leading to progressive accumulation of mutations. Due to the advent of multi-omics datasets, the consequences of somatic mutations and their role in altered tumor metabolism has been well elucidated. Several oncogenes and tumor suppressor genes have been implicated in the progression of ovarian cancer. In this review, we highlight the genetic alterations undergone by the key oncogenes and tumor suppressor genes responsible for the development of ovarian cancer. We also summarize the role of these oncogenes and tumor suppressor genes and their association with a deregulated network of fatty acid, glycolysis, tricarboxylic acid and amino acid metabolism in ovarian cancers. Identification of genomic and metabolic circuits will be useful in clinical stratification of patients with complex etiologies and in identifying drug targets for personalized therapies against cancer.
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Affiliation(s)
- Roopak Murali
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Vaishnavi Balasubramaniam
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Satish Srinivas
- Department of Radiation Oncology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College & Research Institute, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai 600116, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
- Cuor Stem Cellutions Pvt Ltd., Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560065, India
| | - Arun Dharmarajan
- Department of Biomedical Sciences, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
- Stem Cell and Cancer Biology Laboratory, Curtin University, Perth, WA 6102, Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6102, Australia
- Curtin Health and Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
| | - Rajesh Kumar Gandhirajan
- Department of Human Genetics, Faculty of Biomedical Sciences Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Porur, Chennai 600116, India
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29
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Cheung AHK, Hui CHL, Wong KY, Liu X, Chen B, Kang W, To KF. Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis. Int J Cancer 2023; 152:1510-1525. [PMID: 36093588 DOI: 10.1002/ijc.34288] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 08/17/2022] [Accepted: 09/02/2022] [Indexed: 11/11/2022]
Abstract
The use of cell cycle inhibitors has necessitated a better understanding of the cell cycle in tumor biology to optimize the therapeutic approach. Cell cycle aberrations are common in cancers, and it is increasingly acknowledged that these aberrations exert oncogenic effects beyond the cell cycle. Multiple facets such as cancer metabolism, immunity and metastasis are also affected, all of which are beyond the effect of cell proliferation alone. This review comprehensively summarized the important recent findings and advances in these interrelated processes. In cancer metabolism, cell cycle regulators can modulate various pathways in aerobic glycolysis, glucose uptake and gluconeogenesis, mainly through transcriptional regulation and kinase activities. Amino acid metabolism is also regulated through cell cycle progression. On cancer metastasis, metabolic plasticity, immune evasion, tumor microenvironment adaptation and metastatic site colonization are intricately related to the cell cycle, with distinct regulatory mechanisms at each step of invasion and dissemination. Throughout the synthesis of current understanding, knowledge gaps and limitations in the literature are also highlighted, as are new therapeutic approaches such as combinational therapy and challenges in tackling emerging targeted therapy resistance. A greater understanding of how the cell cycle modulates diverse aspects of cancer biology can hopefully shed light on identifying new molecular targets by harnessing the vast potential of the cell cycle.
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Affiliation(s)
- Alvin Ho-Kwan Cheung
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Chris Ho-Lam Hui
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Kit Yee Wong
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoli Liu
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
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30
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Feng W, Zuo M, Li W, Chen S, Wang Z, Yuan Y, Yang Y, Liu Y. A novel score system based on arginine metabolism-related genes to predict prognosis, characterize immune microenvironment, and forecast response to immunotherapy in IDH-wildtype glioblastoma. Front Pharmacol 2023; 14:1145828. [PMID: 37214463 PMCID: PMC10196947 DOI: 10.3389/fphar.2023.1145828] [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: 01/16/2023] [Accepted: 04/06/2023] [Indexed: 05/24/2023] Open
Abstract
Introduction: Glioblastoma is one of the most lethal cancers and leads to more than 200,000 deaths annually. However, despite lots of researchers devoted to exploring novel treatment regime, most of these attempts eventually failed to improve the overall survival of glioblastoma patients in near 20 years. Immunotherapy is an emerging therapy for cancers and have succeeded in many cancers. But most of its application in glioblastoma have been proved with no improvement in overall survival, which may result from the unique immune microenvironment of glioblastoma. Arginine is amino acid and is involved in many physiological processes. Many studies have suggested that arginine and its metabolism can regulate malignancy of multiple cancers and influence the formation of tumor immune microenvironment. However, there is hardly study focusing on the role of arginine metabolism in glioblastoma. Methods: In this research, based on mRNA sequencing data of 560 IDH-wildtype glioblastoma patients from three public cohorts and one our own cohort, we aimed to construct an arginine metabolism-related genes signature (ArMRS) based on four essential arginine metabolism-related genes (ArMGs) that we filtered from all genes with potential relation with arginine metabolism. Subsequently, the glioblastoma patients were classified into ArMRS high-risk and low-risk groups according to calculated optimal cut-off values of ArMRS in these four cohorts. Results: Further validation demonstrated that the ArMRS was an independent prognostic factor and displayed fine efficacy in prediction of glioblastoma patients' prognosis. Moreover, analyses of tumor immune microenvironment revealed that higher ArMRS was correlated with more immune infiltration and relatively "hot" immunological phenotype. We also demonstrated that ArMRS was positively correlated with the expression of multiple immunotherapy targets, including PD1 and B7-H3. Additionally, the glioblastomas in the ArMRS high-risk group would present with more cytotoxic T cells (CTLs) infiltration and better predicted response to immune checkpoint inhibitors (ICIs). Discussion: In conclusion, our study constructed a novel score system based on arginine metabolism, ArMRS, which presented with good efficacy in prognosis prediction and strong potential to predict unique immunological features, resistance to immunotherapy, and guide the application of immunotherapy in IDH-wild type glioblastoma.
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Affiliation(s)
| | | | | | | | | | | | - Yuan Yang
- *Correspondence: Yuan Yang, ; Yanhui Liu,
| | - Yanhui Liu
- *Correspondence: Yuan Yang, ; Yanhui Liu,
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31
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The addition of arginine deiminase potentiates Mithramycin A-induced cell death in patient-derived glioblastoma cells via ATF4 and cytochrome C. Cancer Cell Int 2023; 23:38. [PMID: 36843002 PMCID: PMC9969664 DOI: 10.1186/s12935-023-02873-2] [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: 12/05/2022] [Accepted: 02/14/2023] [Indexed: 02/28/2023] Open
Abstract
BACKGROUND Arginine auxotrophy constitutes a shortcoming for ~ 30% of glioblastoma multiforme (GBM). Indeed, arginine-depleting therapy using arginine deiminase from Streptococcus pyogenes (SpyADI) has proven activity against GBM in preclinical studies. The good safety profile of SpyADI renders this agent an ideal combination partner for cytostatic therapy. METHODS In this study, we combined the antineoplastic antibiotic Mithramycin A (MitA) with SpyADI to boost single-agent activity and analyzed underlying response mechanisms in-depth. RESULTS MitA monotherapy induced a time- and dose-dependent cytotoxicity in eight patient-derived GBM cell lines and had a radiosensitizing effect in all but one cell line. Combination treatment boosted the effects of the monotherapy in 2D- and 3D models. The simultaneous approach was superior to the sequential application and significantly impaired colony formation after repetitive treatment. MitA monotherapy significantly inhibited GBM invasiveness. However, this effect was not enhanced in the combination. Functional analysis identified SpyADI-triggered senescence induction accompanied by increased mitochondrial membrane polarization upon mono- and combination therapy. In HROG63, induction of lysosomes was seen after both monotherapies, indicative of autophagy. These cells seemed swollen and had a more pronounced cortically formed cytoskeleton. Also, cytochrome C and endoplasmatic reticulum-stress-associated proteins ATF4 and Calnexin were enhanced in the combination, contributing to apoptosis. Notably, no significant increases in glioma-stemness marker were seen. CONCLUSIONS Therapeutic utilization of a metabolic defect in GBM along with cytostatic therapy provides a novel combination approach. Whether this SpyADI/MitA regimen will provide a safe alternative to combat GBM, will have to be addressed in subsequent (pre-)clinical trials.
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Li F, Hu X, Wu Z, Yang Q, Sa Q, Ren W, Wang T, Ji Z, Li N, Huang J, Lei L. Untargeted metabolomics reveals alternations in metabolism of bovine mammary epithelial cells upon IFN-γ treatment. BMC Vet Res 2023; 19:44. [PMID: 36765367 PMCID: PMC9921584 DOI: 10.1186/s12917-023-03588-2] [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: 09/10/2022] [Accepted: 01/24/2023] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND IFN-γ is a pleiotropic cytokine that has been shown to affect multiple cellular functions of bovine mammary epithelial cells (BMECs) including impaired milk fat synthesis and induction of malignant transformation via depletion of arginine, one of host conditionally essential amino acids. But the molecular mechanisms of these IFN-γ induced phenotypes are still unknown. METHODS BMECs were treated with IFN-γ for 6 h, 12 h, and 24 h. The metabolomic profiling in BMECs upon IFN-γ induction were assessed using untargeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) metabolomic analysis. Key differentially expressed metabolites (DEMs) were quantified by targeted metabolomics. RESULTS IFN-γ induction resulted in significant differences in the contents of metabolites. Untargeted analysis identified 221 significantly DEMs, most of which are lipids and lipid-like molecules, organic acids and derivatives, organ heterocyclic compounds and benzenoids. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, DEMs were enriched in fructose and mannose metabolism, phosphotransferase system (PTS), β-alanine metabolism, arginine and proline metabolism, methane metabolism, phenylalanine metabolism, and glycolysis/gluconeogenesis. Quantification of selected key DEMs by targeted metabolomics showed significantly decreased levels of D-(-)-mannitol, argininosuccinate, and phenylacetylglycine (PAG), while increased levels in S-hydroxymethylglutathione (S-HMG) and 2,3-bisphospho-D-glyceric acid (2,3-BPG). CONCLUSIONS These results provide insights into the metabolic alterations in BMECs upon IFN-γ induction and indicate potential theoretical basis for clarifying IFN-γ-induced diseases in mammary gland.
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Affiliation(s)
- Fengyang Li
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China
| | - Xiuhong Hu
- Department of First Hospital, Jilin University, 1 Xinmin Street, Changchun, 130021, China
- Shannan Hospital, Shannan, 856099, China
| | - Zengshuai Wu
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China
| | - Qiulei Yang
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China
| | - Qila Sa
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China
| | - Wenbo Ren
- Department of First Hospital, Jilin University, 1 Xinmin Street, Changchun, 130021, China
| | - Tingting Wang
- Department of First Hospital, Jilin University, 1 Xinmin Street, Changchun, 130021, China
| | - Zhengchao Ji
- Department of First Hospital, Jilin University, 1 Xinmin Street, Changchun, 130021, China
| | - Na Li
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China.
| | - Jing Huang
- Department of First Hospital, Jilin University, 1 Xinmin Street, Changchun, 130021, China.
| | - Liancheng Lei
- State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, 1977 Xinzhu Road, Changchun, 130062, China.
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Kurokawa GA, Hamamoto Filho PT, Delafiori J, Galvani AF, de Oliveira AN, Dias-Audibert FL, Catharino RR, Pardini MIMC, Zanini MA, Lima EDO, Ferrasi AC. Differential Plasma Metabolites between High- and Low-Grade Meningioma Cases. Int J Mol Sci 2022; 24:ijms24010394. [PMID: 36613836 PMCID: PMC9820229 DOI: 10.3390/ijms24010394] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/28/2022] Open
Abstract
Meningiomas (MGMs) are currently classified into grades I, II, and III. High-grade tumors are correlated with decreased survival rates and increased recurrence rates. The current grading classification is based on histological criteria and determined only after surgical tumor sampling. This study aimed to identify plasma metabolic alterations in meningiomas of different grades, which would aid surgeons in predefining the ideal surgical strategy. Plasma samples were collected from 51 patients with meningioma and classified into low-grade (LG) (grade I; n = 43), and high-grade (HG) samples (grade II, n = 5; grade III, n = 3). An untargeted metabolomic approach was used to analyze plasma metabolites. Statistical analyses were performed to select differential biomarkers among HG and LG groups. Metabolites were identified using tandem mass spectrometry along with database verification. Five and four differential biomarkers were identified for HG and LG meningiomas, respectively. To evaluate the potential of HG MGM metabolites to differentiate between HG and LG tumors, a receiving operating characteristic curve was constructed, which revealed an area under the curve of 95.7%. This indicates that the five HG MGM metabolites represent metabolic alterations that can differentiate between LG and HG meningiomas. These metabolites may indicate tumor grade even before the appearance of histological features.
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Affiliation(s)
- Gabriel A. Kurokawa
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
| | - Pedro T. Hamamoto Filho
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
- Department of Neurology, Psychology and Psychiatry, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
| | - Jeany Delafiori
- Innovare Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas 13083-877, Brazil
| | - Aline F. Galvani
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
| | - Arthur N. de Oliveira
- Innovare Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas 13083-877, Brazil
| | - Flávia L. Dias-Audibert
- Innovare Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas 13083-877, Brazil
| | - Rodrigo R. Catharino
- Innovare Biomarkers Laboratory, School of Pharmaceutical Sciences, University of Campinas, Campinas 13083-877, Brazil
| | - Maria Inês M. C. Pardini
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
| | - Marco A. Zanini
- Department of Neurology, Psychology and Psychiatry, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
| | - Estela de O. Lima
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
- Correspondence: ; Tel.: +55-14-3880-1453
| | - Adriana C. Ferrasi
- Laboratory of Molecular Analysis and Neuro-oncology, Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618-970, Brazil
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Ragni M, Fornelli C, Nisoli E, Penna F. Amino Acids in Cancer and Cachexia: An Integrated View. Cancers (Basel) 2022; 14:5691. [PMID: 36428783 PMCID: PMC9688864 DOI: 10.3390/cancers14225691] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient's death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.
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Affiliation(s)
- Maurizio Ragni
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Claudia Fornelli
- Department of Clinical and Biological Sciences, University of Torino, 10125 Turin, Italy
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Fabio Penna
- Department of Clinical and Biological Sciences, University of Torino, 10125 Turin, Italy
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Pokrovsky VS, Abo Qoura L, Morozova E, Bunik VI. Predictive markers for efficiency of the amino-acid deprivation therapies in cancer. Front Med (Lausanne) 2022; 9:1035356. [PMID: 36405587 PMCID: PMC9669297 DOI: 10.3389/fmed.2022.1035356] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Amino acid deprivation therapy (AADT) is a promising strategy for developing novel anticancer treatments, based on variations in metabolism of healthy and malignant cells. L-asparaginase was the first amino acid-degrading enzyme that received FDA approval for the treatment of acute lymphoblastic leukemia (ALL). Arginase and arginine deiminase were effective in clinical trials for the treatment of metastatic melanomas and hepatocellular carcinomas. Essential dependence of certain cancer cells on methionine explains the anticancer efficacy of methionine-g-lyase. Along with significant progress in identification of metabolic vulnerabilities of cancer cells, new amino acid-cleaving enzymes appear as promising agents for cancer treatment: lysine oxidase, tyrosine phenol-lyase, cysteinase, and phenylalanine ammonia-lyase. However, sensitivity of specific cancer cell types to these enzymes differs. Hence, search for prognostic and predictive markers for AADT and introduction of the markers into clinical practice are of great importance for translational medicine. As specific metabolic pathways in cancer cells are determined by the enzyme expression, some of these enzymes may define the sensitivity to AADT. This review considers the known predictors for efficiency of AADT, emphasizing the importance of knowledge on cancer-specific amino acid significance for such predictions.
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Affiliation(s)
- Vadim S. Pokrovsky
- Laboratory of Experimental Oncology, Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), Moscow, Russia
- Laboratory of Combined Treatment, N.N. Blokhin National Medical Research Center of Oncology of Ministry of Health of Russian Federation, Moscow, Russia
- Department of Biotechnology, Sirius University of Science and Technology, Sochi, Russia
- *Correspondence: Vadim S. Pokrovsky,
| | - Louay Abo Qoura
- Laboratory of Experimental Oncology, Research Institute of Molecular and Cellular Medicine, People’s Friendship University of Russia (RUDN University), Moscow, Russia
| | - Elena Morozova
- Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Victoria I. Bunik
- A.N. Belozersky Institute of Physicochemical Biology, M.V. Lomonosov Moscow State University, Moscow, Russia
- Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia
- Department of Biological Chemistry, Sechenov First Moscow State Medical University, Moscow, Russia
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Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism. Oncogene 2022; 41:4994-5007. [PMID: 36319669 PMCID: PMC9652143 DOI: 10.1038/s41388-022-02489-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 09/25/2022] [Accepted: 09/26/2022] [Indexed: 11/06/2022]
Abstract
Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma.
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37
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Diwan D, Cheng L, Usmani Z, Sharma M, Holden N, Willoughby N, Sangwan N, Baadhe RR, Liu C, Gupta VK. Microbial cancer therapeutics: A promising approach. Semin Cancer Biol 2022; 86:931-950. [PMID: 33979677 DOI: 10.1016/j.semcancer.2021.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 05/04/2021] [Indexed: 01/27/2023]
Abstract
The success of conventional cancer therapeutics is hindered by associated dreadful side-effects of antibiotic resistance and the dearth of antitumor drugs' selectivity and specificity. Hence, the conceptual evolution of anti-cancerous therapeutic agents that selectively target cancer cells without impacting the healthy cells or tissues, has led to a new wave of scientific interest in microbial-derived bioactive molecules. Such strategic solutions may pave the way to surmount the shortcomings of conventional therapies and raise the potential and hope for the cure of wide range of cancer in a selective manner. This review aims to provide a comprehensive summary of anti-carcinogenic properties and underlying mechanisms of bioactive molecules of microbial origin, and discuss the current challenges and effective therapeutic application of combinatorial strategies to attain minimal systemic side-effects.
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Affiliation(s)
- Deepti Diwan
- Washington University, School of Medicine, Saint Louis, MO, USA
| | - Lei Cheng
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 230032, China
| | - Zeba Usmani
- Department of Chemistry and Biotechnology, Tallinn University of Technology, 12618, Tallinn, Estonia
| | - Minaxi Sharma
- Department of Food Technology, Akal College of Agriculture, Eternal University, Baru Sahib, Himachal Pradesh, 173101, India
| | - Nicola Holden
- Centre for Safe and Improved Food, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK
| | - Nicholas Willoughby
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Neelam Sangwan
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, 123031, India
| | - Rama Raju Baadhe
- Department of Biotechnology, National Institute of Technology, Warangal, Telangana, 506004, India
| | - Chenchen Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Vijai Kumar Gupta
- Centre for Safe and Improved Food, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK; Biorefining and Advanced Materials Research Center, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK.
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38
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Hu X, Wang Z, Chen H, Zhao A, Sun N, Deng C. Diagnosing, Typing, and Staging of Renal Cell Carcinoma by Designer Matrix-Based Urinary Metabolic Analysis. Anal Chem 2022; 94:14846-14853. [PMID: 36260912 DOI: 10.1021/acs.analchem.2c01563] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Molecular diagnosing, typing, and staging have been considered to be the ideal alternatives of imaging-based detection methods in clinics. Designer matrix-based analytical tools, with high speed, throughout, efficiency and low/noninvasiveness, have attracted much attention recently for in vitro metabolite detection. Herein, we develop an advanced metabolic analysis tool based on highly porous metal oxides derived from available metal-organic frameworks (MOFs), which elaborately inherit the morphology and porosity of MOFs and newly incorporate laser adsorption capacity of metal oxides. Through optimized conditions, direct high-quality fingerprinting spectra in 0.5 μL of urine are acquired. Using these fingerprinting spectra, we can discriminate the renal cell carcinoma (RCC) from healthy controls with higher than 0.99 of area under the curve (AUC) values (R2Y(cum) = 0.744, Q2 (cum) = 0.880), as well, from patients with other tumors (R2Y(cum) = 0.748, Q2(cum) = 0.871). We also realize the typing of three RCC subtypes, including clear cell RCC, chromophobe RCC (R2Y(cum) = 0.620, Q2(cum) = 0.656), and the staging of RCC (R2Y(cum) = 0.755, Q2(cum) = 0.857). Moreover, the tumor sizes (threshold value is 3 cm) can be remarkably recognized by this advanced metabolic analysis tool (R2Y(cum) = 0.710, Q2(cum) = 0.787). Our work brings a bright prospect for designer matrix-based analytical tools in disease diagnosis, typing and staging.
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Affiliation(s)
- Xufang Hu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, and Department of Chemistry, Fudan University, Shanghai 200032, China
| | - Zongping Wang
- Department of Urology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310000, China
| | - Haolin Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, and Department of Chemistry, Fudan University, Shanghai 200032, China
| | - An Zhao
- Experimental Research Center, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310000, China.,Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Nianrong Sun
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, and Department of Chemistry, Fudan University, Shanghai 200032, China
| | - Chunhui Deng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, and Department of Chemistry, Fudan University, Shanghai 200032, China
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Lee H, Park G, Kim S, Son B, Joo J, Park HH, Park TH. Enhancement of anti-tumor activity in melanoma using arginine deiminase fused with 30Kc19α protein. Appl Microbiol Biotechnol 2022; 106:7531-7545. [PMID: 36227339 DOI: 10.1007/s00253-022-12218-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/28/2022]
Abstract
Arginine deiminase (ADI) is a microbial-derived enzyme which catalyzes the conversion of L-arginine into L-citrulline. ADI originating from Mycoplasma has been reported to present anti-tumor activity against arginine-auxotrophic tumors, including melanoma. Melanoma cells are sensitive to arginine depletion due to reduced expression of argininosuccinate synthase 1 (ASS1), a key enzyme for arginine biosynthesis. However, clinical applications of recombinant ADI for melanoma treatment present some limitations. Since recombinant ADI is not human-derived, it shows instability, proteolytic degradation, and antigenicity in human serum. In addition, there is a problem of drug resistance issue due to the intracellular expression of once-silenced ASS1. Moreover, recombinant ADI proteins are mainly expressed as inclusion body forms in Escherichia coli and require a time-consuming refolding process to turn them back into active form. Herein, we propose fusion of recombinant ADI from Mycoplasma hominis and 30Kc19α, a cell-penetrating protein which also increases stability and soluble expression of cargo proteins, to overcome these problems. We inserted matrix metalloproteinase-2 cleavable linker between ADI and 30Kc19α to increase enzyme activity in melanoma cells. Compared to ADI, ADI-LK-30Kc19α showed enhanced solubility, stability, and cell penetration. The fusion protein demonstrated selective cytotoxicity and reduced drug resistance in melanoma cells, thus would be a promising strategy for the improved efficacy in melanoma treatment. KEY POINTS: • Fusion of ADI with 30Kc19α enhances soluble expression and productivity of recombinant ADI in E. coli • 30Kc19α protects ADI from the proteolytic degradation by shielding effect, helping ADI to remain active • Intracellular delivery of ADI by 30Kc19α overcomes ADI resistance in melanoma cells by degrading intracellularly expressed arginine.
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Affiliation(s)
- Haein Lee
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Geunhwa Park
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea
| | - Seulha Kim
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Boram Son
- Department of Bioengineering, Hanyang University, Seoul, Republic of Korea
| | - Jinmyoung Joo
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea
| | - Hee Ho Park
- Department of Bioengineering, Hanyang University, Seoul, Republic of Korea. .,Education and Research Group for Biopharmaceutical Innovation Leader, Hanyang University, Seoul, Republic of Korea.
| | - Tai Hyun Park
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea. .,Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea. .,BioMax/N-Bio Institute, Institute of Bioengineering, Seoul National University, Seoul, Republic of Korea.
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40
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Jiménez JA, Lawlor ER, Lyssiotis CA. Amino acid metabolism in primary bone sarcomas. Front Oncol 2022; 12:1001318. [PMID: 36276057 PMCID: PMC9581121 DOI: 10.3389/fonc.2022.1001318] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 08/19/2022] [Indexed: 12/30/2022] Open
Abstract
Primary bone sarcomas, including osteosarcoma (OS) and Ewing sarcoma (ES), are aggressive tumors with peak incidence in childhood and adolescence. The intense standard treatment for these patients consists of combined surgery and/or radiation and maximal doses of chemotherapy; a regimen that has not seen improvement in decades. Like other tumor types, ES and OS are characterized by dysregulated cellular metabolism and a rewiring of metabolic pathways to support the biosynthetic demands of malignant growth. Not only are cancer cells characterized by Warburg metabolism, or aerobic glycolysis, but emerging work has revealed a dependence on amino acid metabolism. Aside from incorporation into proteins, amino acids serve critical functions in redox balance, energy homeostasis, and epigenetic maintenance. In this review, we summarize current studies describing the amino acid metabolic requirements of primary bone sarcomas, focusing on OS and ES, and compare these dependencies in the normal bone and malignant tumor contexts. We also examine insights that can be gleaned from other cancers to better understand differential metabolic susceptibilities between primary and metastatic tumor microenvironments. Lastly, we discuss potential metabolic vulnerabilities that may be exploited therapeutically and provide better-targeted treatments to improve the current standard of care.
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Affiliation(s)
- Jennifer A. Jiménez
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Elizabeth R. Lawlor
- Department of Pediatrics, University of Washington, Seattle, WA, United States,Seattle Children’s Research Institute, Seattle, WA, United States,*Correspondence: Elizabeth R. Lawlor, ; Costas A. Lyssiotis,
| | - Costas A. Lyssiotis
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States,Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States,*Correspondence: Elizabeth R. Lawlor, ; Costas A. Lyssiotis,
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41
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Safrhansova L, Hlozkova K, Starkova J. Targeting amino acid metabolism in cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 373:37-79. [PMID: 36283767 DOI: 10.1016/bs.ircmb.2022.08.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.
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Affiliation(s)
- Lucie Safrhansova
- CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Dept. of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Katerina Hlozkova
- CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Dept. of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Julia Starkova
- CLIP - Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Dept. of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic.
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42
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Shu Y, Li F, Han Y, Wang P, Gao F, Yan M, Liang M, Ma Q, Zhang Y, Ding X, Lei H. Design, synthesis and cytotoxic evaluation of novel betulonic acid-diazine derivatives as potential antitumor agents. Front Chem 2022; 10:969770. [PMID: 36147251 PMCID: PMC9486541 DOI: 10.3389/fchem.2022.969770] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
With the purpose to improve antiproliferative activity, 26 new betulonic acid-diazine derivatives were designed and synthesized from betulinic acid. The anticancer activity of these semi-synthetic compounds was evaluated by MTT assay in both tumor cell lines and normal cell line. The results indicated that majority of new compounds exhibited improved antitumor activity compared with the parent compound betulonic acid. Compound BoA2C, in particular, had the most significant action with IC50 value of 3.39 μM against MCF-7 cells, while it showed lower cytotoxicity on MDCK cell line than cisplatin. Furthermore, we discovered that BoA2C strongly increased MCF-7 cell damage mostly by influencing arginine and fatty acid metabolism. In addition, the structure-activity relationships were briefly discussed. The results of this study suggested that the introduction of different diazines at C-28 could selectively inhibit different kinds of cancer cells and might be an effective way to synthesize potent anticancer lead compound from betulonic acid.
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Affiliation(s)
- Yisong Shu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Feifei Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yaotian Han
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Penglong Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Feng Gao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Mengmeng Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Miao Liang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Qiang Ma
- Chinese Academy of Inspection and Quarantine, Beijing, China
- *Correspondence: Qiang Ma, ; Yuzhong Zhang, ; Xia Ding, ; Haimin Lei ,
| | - Yuzhong Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Qiang Ma, ; Yuzhong Zhang, ; Xia Ding, ; Haimin Lei ,
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Qiang Ma, ; Yuzhong Zhang, ; Xia Ding, ; Haimin Lei ,
| | - Haimin Lei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Qiang Ma, ; Yuzhong Zhang, ; Xia Ding, ; Haimin Lei ,
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43
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Kim G, Jang SK, Kim YJ, Jin HO, Bae S, Hong J, Park IC, Lee JH. Inhibition of Glutamine Uptake Resensitizes Paclitaxel Resistance in SKOV3-TR Ovarian Cancer Cell via mTORC1/S6K Signaling Pathway. Int J Mol Sci 2022; 23:ijms23158761. [PMID: 35955892 PMCID: PMC9369036 DOI: 10.3390/ijms23158761] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer is a carcinoma that affects women and that has a high mortality rate. Overcoming paclitaxel resistance is important for clinical application. However, the effect of amino acid metabolism regulation on paclitaxel-resistant ovarian cancer is still unknown. In this study, the effect of an amino acid-deprived condition on paclitaxel resistance in paclitaxel-resistant SKOV3-TR cells was analyzed. We analyzed the cell viability of SKOV3-TR in culture conditions in which each of the 20 amino acids were deprived. As a result, the cell viability of the SKOV3-TR was significantly reduced in cultures deprived of arginine, glutamine, and lysine. Furthermore, we showed that the glutamine-deprived condition inhibited mTORC1/S6K signaling. The decreased cell viability and mTORC1/S6K signaling under glutamine-deprived conditions could be restored by glutamine and α-KG supplementation. Treatment with PF-4708671, a selective S6K inhibitor, and the selective glutamine transporter ASCT2 inhibitor V-9302 downregulated mTOR/S6K signaling and resensitized SKOV3-TR to paclitaxel. Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer.
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Affiliation(s)
- Gyeongmi Kim
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
| | - Se-Kyeong Jang
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
- Department of Food and Microbial Technology, Seoul Women’s University, 621 Hwarangro, Nowon-gu, Seoul 01797, Korea
| | - Yu Jin Kim
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
- Department of Biological Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
| | - Hyeon-Ok Jin
- KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
| | - Seunghee Bae
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
| | - Jungil Hong
- Department of Food and Microbial Technology, Seoul Women’s University, 621 Hwarangro, Nowon-gu, Seoul 01797, Korea
| | - In-Chul Park
- Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
- Correspondence: (I.-C.P.); (J.H.L.)
| | - Jae Ho Lee
- Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea
- Correspondence: (I.-C.P.); (J.H.L.)
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44
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Identification of Candidate Biomarker and Drug Targets for Improving Endometrial Cancer Racial Disparities. Int J Mol Sci 2022; 23:ijms23147779. [PMID: 35887124 PMCID: PMC9318530 DOI: 10.3390/ijms23147779] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/17/2022] Open
Abstract
Racial disparities in incidence and survival exist for many human cancers. Racial disparities are undoubtedly multifactorial and due in part to differences in socioeconomic factors, access to care, and comorbidities. Within the U.S., fundamental causes of health inequalities, including socio-economic factors, insurance status, access to healthcare and screening and treatment biases, are issues that contribute to cancer disparities. Yet even these epidemiologic differences do not fully account for survival disparities, as for nearly every stage, grade and histologic subtype, survival among Black women is significantly lower than their White counterparts. To address this, we sought to investigate the proteomic profiling molecular features of endometrial cancer in order to detect modifiable and targetable elements of endometrial cancer in different racial groups, which could be essential for treatment planning. The majority of proteins identified to be significantly altered among the racial groups and that can be regulated by existing drugs or investigational agents are enzymes that regulate metabolism and protein synthesis. These drugs have the potential to improve the worse outcomes of endometrial cancer patients based on race.
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45
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Hou X, Chen S, Zhang P, Guo D, Wang B. Targeted Arginine Metabolism Therapy: A Dilemma in Glioma Treatment. Front Oncol 2022; 12:938847. [PMID: 35898872 PMCID: PMC9313538 DOI: 10.3389/fonc.2022.938847] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/20/2022] [Indexed: 11/29/2022] Open
Abstract
Efforts in the treatment of glioma which is the most common primary malignant tumor of the central nervous system, have not shown satisfactory results despite a comprehensive treatment model that combines various treatment methods, including immunotherapy. Cellular metabolism is a determinant of the viability and function of cancer cells as well as immune cells, and the interplay of immune regulation and metabolic reprogramming in tumors has become an active area of research in recent years. From the perspective of metabolism and immunity in the glioma microenvironment, we elaborated on arginine metabolic reprogramming in glioma cells, which leads to a decrease in arginine levels in the tumor microenvironment. Reduced arginine availability significantly inhibits the proliferation, activation, and function of T cells, thereby promoting the establishment of an immunosuppressive microenvironment. Therefore, replenishment of arginine levels to enhance the anti-tumor activity of T cells is a promising strategy for the treatment of glioma. However, due to the lack of expression of argininosuccinate synthase, gliomas are unable to synthesize arginine; thus, they are highly dependent on the availability of arginine in the extracellular environment. This metabolic weakness of glioma has been utilized by researchers to develop arginine deprivation therapy, which ‘starves’ tumor cells by consuming large amounts of arginine in circulation. Although it has shown good results, this treatment modality that targets arginine metabolism in glioma is controversial. Exploiting a suitable strategy that can not only enhance the antitumor immune response, but also “starve” tumor cells by regulating arginine metabolism to cure glioma will be promising.
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46
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Chan PY, Phillips MM, Ellis S, Johnston A, Feng X, Arora A, Hay G, Cohen VML, Sagoo MS, Bomalaski JS, Sheaff MT, Szlosarek PW. A Phase 1 study of ADI-PEG20 (pegargiminase) combined with cisplatin and pemetrexed in ASS1-negative metastatic uveal melanoma. Pigment Cell Melanoma Res 2022; 35:461-470. [PMID: 35466524 PMCID: PMC9322321 DOI: 10.1111/pcmr.13042] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/19/2022] [Accepted: 04/21/2022] [Indexed: 12/14/2022]
Abstract
Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI‐PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose‐expansion study of patients with argininosuccinate synthetase (ASS1)‐deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m2) and Cis (75 mg/m2) every 3 weeks plus weekly intramuscular ADI (36 mg/m2), followed by maintenance ADI until progression (NCT02029690). Ten of fourteen ASS1‐deficient patients with UM liver metastases and a median of one line of prior immunotherapy received ADIPemCis. Only one ≥ grade 3 adverse event of febrile neutropenia was reported. Seven patients had stable disease with a median progression‐free survival of 3.0 months (range, 1.3–8.1) and a median overall survival of 11.5 months (range, 3.2–36.9). Despite anti‐ADI‐PEG20 antibody emergence, plasma arginine concentrations remained suppressed by 18 weeks with a reciprocal increase in plasma citrulline. Tumour rebiopsies at progression revealed ASS1 re‐expression as an escape mechanism. ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional anti‐metabolite strategies.
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Affiliation(s)
- Pui Ying Chan
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Melissa M Phillips
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Stephen Ellis
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | | | - Xiaoxing Feng
- Polaris Pharmaceuticals Inc, San Diego, California, USA
| | - Amit Arora
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Gordon Hay
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Victoria M L Cohen
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Mandeep S Sagoo
- Department of Ocular Oncology, Moorfields Eye Hospital, Moorfields Eye Hospital NHS Foundation Trust, London, UK.,NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK
| | | | - Michael T Sheaff
- Department of Histopathology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Peter W Szlosarek
- Department of Medical Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.,Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
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47
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Zhao P, Shen Y, Li M, Dan H, Zhao Z, Zhang J. Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism Underlying Tadalafil in Colorectal Cancer. Front Pharmacol 2022; 13:793499. [PMID: 35694253 PMCID: PMC9184725 DOI: 10.3389/fphar.2022.793499] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/21/2022] [Indexed: 11/25/2022] Open
Abstract
The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in colorectal cancer were not fully understood. In this study, we assessed the anti-tumor activity of tadalafil in human colorectal cancer cells. A systematic perspective of the tadalafil-induced anti-tumor mechanism was provided by the integration of transcriptomics and metabolomics. We found that differentially expressed genes (DEGs) were mainly involved in microRNAs in cancer, purine metabolism, glycosphingolipid biosynthesis, arginine biosynthesis, and amino acid metabolism. Amino acid metabolism, especially alanine, aspartate, and glutamate metabolism was the most of the differentially accumulated metabolites (DAMs) through the analysis of metabolomics. The conjoint analysis of DEGs and DAMs presented that they were also mainly involved in alanine, aspartate, and glutamate metabolism. Amino acid metabolism-related genes, GPT, GGT5, and TAT, were significantly decreased after tadalafil treatment. In particular, the disturbance of alanine, aspartate, and glutamate metabolism may be the explanation for the major mechanism resulting from tadalafil anti-tumor activity.
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Affiliation(s)
- Pan Zhao
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, China
| | - Yao Shen
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, China
| | - Mengyang Li
- The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Hanjun Dan
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, China
| | - Zhiming Zhao
- The Faculty of Hepatopancreatobiliary Surgery, The First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- *Correspondence: Zhiming Zhao, ; Jian Zhang,
| | - Jian Zhang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, China
- *Correspondence: Zhiming Zhao, ; Jian Zhang,
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48
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Kumar V, Singh P, Gupta SK, Ali V, Jyotirmayee, Verma M. Alterations in cellular metabolisms after Imatinib therapy: a review. Med Oncol 2022; 39:95. [DOI: 10.1007/s12032-022-01699-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/25/2022] [Indexed: 12/29/2022]
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49
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Russell RC, Guan KL. The multifaceted role of autophagy in cancer. EMBO J 2022; 41:e110031. [PMID: 35535466 PMCID: PMC9251852 DOI: 10.15252/embj.2021110031] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 03/20/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022] Open
Abstract
Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work in genetically engineered mouse models and in vitro cell studies have now shown that autophagy can be either cancer-promoting or inhibiting. Here, we summarize the effects of autophagy on cancer initiation, progression, immune infiltration, and metabolism. We also discuss the efforts to pharmacologically target autophagy in the clinic and highlight future areas for exploration.
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Affiliation(s)
- Ryan C Russell
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Center for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada.,Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Kun-Liang Guan
- Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
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50
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Pardo JC, Ruiz de Porras V, Gil J, Font A, Puig-Domingo M, Jordà M. Lipid Metabolism and Epigenetics Crosstalk in Prostate Cancer. Nutrients 2022; 14:851. [PMID: 35215499 PMCID: PMC8874497 DOI: 10.3390/nu14040851] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/27/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) is the most commonly diagnosed malignant neoplasm in men in the Western world. Localized low-risk PCa has an excellent prognosis thanks to effective local treatments; however, despite the incorporation of new therapeutic strategies, metastatic PCa remains incurable mainly due to disease heterogeneity and the development of resistance to therapy. The mechanisms underlying PCa progression and therapy resistance are multiple and include metabolic reprogramming, especially in relation to lipid metabolism, as well as epigenetic remodelling, both of which enable cancer cells to adapt to dynamic changes in the tumour. Interestingly, metabolism and epigenetics are interconnected. Metabolism can regulate epigenetics through the direct influence of metabolites on epigenetic processes, while epigenetics can control metabolism by directly or indirectly regulating the expression of metabolic genes. Moreover, epidemiological studies suggest an association between a high-fat diet, which can alter the availability of metabolites, and PCa progression. Here, we review the alterations of lipid metabolism and epigenetics in PCa, before focusing on the mechanisms that connect them. We also discuss the influence of diet in this scenario. This information may help to identify prognostic and predictive biomarkers as well as targetable vulnerabilities.
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Affiliation(s)
- Juan C. Pardo
- Department of Medical Oncology, Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.C.P.); (A.F.)
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain;
| | - Vicenç Ruiz de Porras
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain;
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.G.); (M.P.-D.)
| | - Joan Gil
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.G.); (M.P.-D.)
- Department of Endocrinology and Medicine, CIBERER U747, ISCIII, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-SPau, Universitat Autònoma de Barcelona, 08041 Barcelona, Spain
| | - Albert Font
- Department of Medical Oncology, Catalan Institute of Oncology, University Hospital Germans Trias i Pujol, Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.C.P.); (A.F.)
- Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain;
| | - Manel Puig-Domingo
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.G.); (M.P.-D.)
- Department of Endocrinology and Nutrition, University Germans Trias i Pujol Hospital, Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain
| | - Mireia Jordà
- Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les Escoles s/n, 08916 Badalona, Spain; (J.G.); (M.P.-D.)
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