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Xie X, Liu W, Yuan Z, Chen H, Mao W. Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications. Mol Cancer 2025; 24:71. [PMID: 40057791 PMCID: PMC11889836 DOI: 10.1186/s12943-025-02269-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/11/2025] [Indexed: 04/02/2025] Open
Abstract
Epigenomic modifications-such as DNA methylation, histone acetylation, and histone methylation-and their implications in tumorigenesis, progression, and treatment have emerged as a pivotal field in cancer research. Tumors undergo metabolic reprogramming to sustain proliferation and metastasis in nutrient-deficient conditions, while suppressing anti-tumor immunity in the tumor microenvironment (TME). Concurrently, immune cells within the immunosuppressive TME undergo metabolic adaptations, leading to alterations in their immune function. The complicated interplay between metabolites and epigenomic modulation has spotlighted the significance of epigenomic regulation in tumor immunometabolism. In this review, characteristics of the epigenomic modification associated with tumors are systematically summarized alongside with their regulatory roles in tumor metabolic reprogramming and immunometabolism. Classical and emerging approaches are delineated to broaden the boundaries of research on the crosstalk research on the crosstalk between tumor immunometabolism and epigenomics. Furthermore, we discuss potential therapeutic strategies that target tumor immunometabolism to modulate epigenomic modifications, highlighting the burgeoning synergy between metabolic therapies and immunotherapy as a promising avenue for cancer treatment.
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Affiliation(s)
- Xiaowen Xie
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
| | - Weici Liu
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
- Center of Clinical Research, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Zhiyuan Yuan
- Institute of Science and Technology for Brain-Inspired Intelligence; MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence; MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China.
| | - Hanqing Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China.
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2
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Xing Z, Tu BP. Mechanisms and rationales of SAM homeostasis. Trends Biochem Sci 2025; 50:242-254. [PMID: 39818457 PMCID: PMC11890959 DOI: 10.1016/j.tibs.2024.12.009] [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: 08/14/2024] [Revised: 11/21/2024] [Accepted: 12/11/2024] [Indexed: 01/18/2025]
Abstract
S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms. This suggests that the need to maintain SAM homeostasis represents a significant evolutionary pressure across all kingdoms of life. Here, we review how SAM controls cellular functions at the molecular level and discuss strategies to maintain SAM homeostasis. We propose that SAM exerts a broad and underappreciated influence in cellular regulation that remains to be fully elucidated.
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Affiliation(s)
- Zheng Xing
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
| | - Benjamin P Tu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX USA.
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3
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Pham DX, Hsu T. Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma. J Biomed Sci 2025; 32:17. [PMID: 39920694 PMCID: PMC11806631 DOI: 10.1186/s12929-024-01111-9] [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: 10/02/2024] [Accepted: 12/11/2024] [Indexed: 02/09/2025] Open
Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney malignancy. ccRCC is considered a major health concern worldwide because its numbers of incidences and deaths continue to rise and are predicted to continue rising in the foreseeable future. Therefore new strategy for early diagnosis and therapeutics for this disease is urgently needed. The discovery of cancer stem cells (CSCs) offers hope for early cancer detection and treatment. However, there has been no definitive identification of these cancer progenitors for ccRCC. A majority of ccRCC is characterized by the loss of the von Hippel-Lindau (VHL) tumor suppressor gene function. Recent advances in genome analyses of ccRCC indicate that in ccRCC, tumor-initiating cells (TICs) and metastasis-initiating cells (MICs) are two distinct groups of progenitors. MICs result from various genetic changes during subclonal evolution, while TICs reside in the stem of the ccRCC phylogenetic tree of clonal development. TICs likely originate from kidney tubule progenitor cells bearing VHL gene inactivation, including chromatin 3p loss. Recent studies also point to the importance of microenvironment reconstituted by the VHL-deficient kidney tubule cells in promoting ccRCC initiation and progression. These understandings should help define the progenitors of ccRCC and facilitate early detection and treatment of this disease.
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Affiliation(s)
- Dinh-Xuan Pham
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC
| | - Tien Hsu
- Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan, ROC.
- Graduate Institute of Biomedical Sciences, China Medical University-Taiwan, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ROC.
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Kobayashi K, Taguchi YH. Gene Selection of Methionine-Dependent Melanoma and Independent Melanoma by Variable Selection Using Tensor Decomposition. Genes (Basel) 2024; 15:1543. [PMID: 39766809 PMCID: PMC11675770 DOI: 10.3390/genes15121543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/14/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Methionine is an essential amino acid. Dietary methionine restriction is associated with decreased tumor growth in preclinical studies and extended lifespans in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is not fully understood. In this study, we applied tensor decomposition-based feature extraction for gene selection from the gene expression profiles of two cell lines of RNA sequencing. We compared two human melanoma cell lines, A101D and MeWo. A101D is a typical cancer cell line that exhibits methionine dependence. MeWo is a methionine-independent cell line. We used the application on R, TDbasedUFE, to perform an enrichment analysis of the selected gene set. Consequently, concordance with existing research on the differences between methionine-dependent melanoma and methionine-independent melanoma was confirmed. Targeting methionine metabolism is considered a promising strategy for treating melanoma and other cancers.
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Affiliation(s)
- Kenta Kobayashi
- Graduate School of Science and Engineering, Chuo University, Tokyo 112-8551, Japan
| | - Y-h. Taguchi
- Department of Physics, Chuo University, Tokyo 112-8551, Japan;
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Pulous FE, Steurer B, Pun FW, Zhang M, Ren F, Zhavoronkov A. MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer. Drug Discov Today 2024; 29:104189. [PMID: 39306235 DOI: 10.1016/j.drudis.2024.104189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/05/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Metabolic and transcriptional reprogramming are crucial hallmarks of carcinogenesis that present exploitable vulnerabilities for the development of targeted anticancer therapies. Through controlling the balance of the cellular methionine (MET) metabolite pool, MET adenosyl transferase 2 alpha (MAT2A) regulates crucial steps during metabolism and the epigenetic control of transcription. The aberrant function of MAT2A has been shown to drive malignant transformation through metabolic addiction, transcriptional rewiring, and immune modulation of the tumor microenvironment (TME). Moreover, MAT2A sustains the survival of 5'-methylthioadenosine phosphorylase (MTAP)-deficient tumors, conferring synthetic lethality to cancers with MTAP loss, a genetic alteration that occurs in ∼15% of all cancers. Thus, the pharmacological inhibition of MAT2A is emerging as a desirable therapeutic strategy to combat tumor growth. Here, we review the latest insights into MAT2A biology, focusing on its roles in both metabolic addiction and gene expression modulation in the TME, outline the current landscape of MAT2A inhibitors, and highlight the most recent clinical developments and opportunities for MAT2A inhibition as a novel anti-tumor therapy.
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Affiliation(s)
- Fadi E Pulous
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA
| | - Barbara Steurer
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA
| | - Frank W Pun
- Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Man Zhang
- Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, China
| | - Feng Ren
- Insilico Medicine Shanghai Ltd, 9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New Area, China
| | - Alex Zhavoronkov
- Insilico Medicine US Inc, 1000 Massachusetts Avenue, Suite 126, Cambridge, MA 02138, USA; Insilico Medicine Hong Kong Ltd, Unit 310, 3/F, Building 8W, Hong Kong Science and Technology Park, Hong Kong SAR, China; Insilico Medicine AI Ltd, Level 6, Unit 08, Block A, IRENA HQ Building, Masdar City, Abu Dhabi, UAE.
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Zhang C, Lu X, Ni T, Wang Q, Gao X, Sun X, Li J, Mao F, Hou J, Wang Y. Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B. Pharmacol Res 2024; 209:107420. [PMID: 39293586 DOI: 10.1016/j.phrs.2024.107420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/14/2024] [Accepted: 09/15/2024] [Indexed: 09/20/2024]
Abstract
Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory β subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 μM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.
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Affiliation(s)
- Chunxue Zhang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Xiaojing Lu
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Ting Ni
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Qi Wang
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaoyan Gao
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Xiao Sun
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China
| | - Jian Li
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Fei Mao
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
| | - Jin Hou
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai 200433, China.
| | - Yudong Wang
- Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China.
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Perez LM, Venugopal SV, Martin AS, Freedland SJ, Di Vizio D, Freeman MR. Mechanisms governing lineage plasticity and metabolic reprogramming in cancer. Trends Cancer 2024; 10:1009-1022. [PMID: 39218770 DOI: 10.1016/j.trecan.2024.08.001] [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: 04/19/2024] [Revised: 07/30/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024]
Abstract
Dynamic alterations in cellular phenotypes during cancer progression are attributed to a phenomenon known as 'lineage plasticity'. This process is associated with therapeutic resistance and involves concurrent shifts in metabolic states that facilitate adaptation to various stressors inherent in malignant growth. Certain metabolites also serve as synthetic reservoirs for chromatin modification, thus linking metabolic states with epigenetic regulation. There remains a critical need to understand the mechanisms that converge on lineage plasticity and metabolic reprogramming to prevent the emergence of lethal disease. This review attempts to offer an overview of our current understanding of the interplay between metabolic reprogramming and lineage plasticity in the context of cancer, highlighting the intersecting drivers of cancer hallmarks, with an emphasis on solid tumors.
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Affiliation(s)
- Lillian M Perez
- Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Smrruthi V Venugopal
- Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Anna St Martin
- Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen J Freedland
- Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dolores Di Vizio
- Department of Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Michael R Freeman
- Departments of Urology and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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Feng L, Chen Y, Mei X, Wang L, Zhao W, Yao J. Prognostic Signature in Osteosarcoma Based on Amino Acid Metabolism-Associated Genes. Cancer Biother Radiopharm 2024; 39:517-531. [PMID: 38512709 DOI: 10.1089/cbr.2024.0002] [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: 03/23/2024] Open
Abstract
Background: Osteosarcoma (OS) is undeniably a formidable bone malignancy characterized by a scarcity of effective treatment options. Reprogramming of amino acid (AA) metabolism has been associated with OS development. The present study was designed to identify metabolism-associated genes (MAGs) that are differentially expressed in OS and to construct a MAG-based prognostic risk signature for this disease. Methods: Expression profiles and clinicopathological data were downloaded from Gene Expression Omnibus (GEO) and UCSC Xena databases. A set of AA MAGs was obtained from the MSigDB database. Differentially expressed genes (DEGs) in GEO dataset were identified using "limma." Prognostic MAGs from UCSC Xena database were determined through univariate Cox regression and used in the prognostic signature development. This signature was validated using another dataset from GEO database. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, single sample gene set enrichment analysis, and GDSC2 analyses were performed to explore the biological functions of the MAGs. A MAG-based nomogram was established to predict 1-, 3-, and 5-year survival. Real-time quantitative polymerase chain reaction, Western blot, and immunohistochemical staining confirmed the expression of MAGs in primary OS and paired adjacent normal tissues. Results: A total of 790 DEGs and 62 prognostic MAGs were identified. A MAG-based signature was constructed based on four MAGs: PIPOX, PSMC2, SMOX, and PSAT1. The prognostic value of this signature was successfully validated, with areas under the receiver operating characteristic curves for 1-, 3-, and 5-year survival of 0.714, 0.719, and 0.715, respectively. This MAG-based signature was correlated with the infiltration of CD56dim natural killer cells and resistance to several antiangiogenic agents. The nomogram was accurate in predictions, with a C-index of 0.77. The expression of MAGs verified by experiment was consistent with the trends observed in GEO database. Conclusion: Four AA MAGs were prognostic of survival in OS patients. This MAG-based signature has the potential to offer valuable insights into the development of treatments for OS.
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Affiliation(s)
- Liwen Feng
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuting Chen
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangping Mei
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenjing Zhao
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Jiannan Yao
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Xuan YF, Lu S, Ou YJ, Bao XB, Huan XJ, Song SS, Miao ZH, Wang YQ. The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity. Biochem Biophys Res Commun 2024; 716:150011. [PMID: 38704890 DOI: 10.1016/j.bbrc.2024.150011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.
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Affiliation(s)
- Yi-Fei Xuan
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Shan Lu
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Ying-Jie Ou
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xu-Bin Bao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Xia-Juan Huan
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Shan-Shan Song
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Ze-Hong Miao
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
| | - Ying-Qing Wang
- State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
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Faridoon, Zheng J, Zhang T, Tong S, Liu T, Cui J, Xu H, Hu D, Shen Y, Yin Y, Zhao D, Tan C, Dong X, Chen J, Ji F, Tong C, Li JJ, Li J, Zhang G. Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy. J Med Chem 2024; 67:9431-9446. [PMID: 38818879 DOI: 10.1021/acs.jmedchem.4c00552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a Kpuu of 0.64 in rats.
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Affiliation(s)
- Faridoon
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Jiyue Zheng
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Tao Zhang
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Shuilong Tong
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Tao Liu
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Jiuen Cui
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Haojie Xu
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Di Hu
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Ying Shen
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Yajing Yin
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Danhua Zhao
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Chensheng Tan
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Xue Dong
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Jiali Chen
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Feihong Ji
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Chenhua Tong
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Jie Jack Li
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Jiapeng Li
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
| | - Guiping Zhang
- Center for Drug Design and Development, Suzhou Genhouse Bio Co., Ltd., No. 1 Xinze Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China
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11
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Guo J, Buettner R, Du L, Li Z, Liu W, Su R, Chen Z, Che Y, Zhang Y, Ma R, Nguyen LXT, Moore RE, Khyatiben P, Chen MH, Patrick P, Wu X, Marcucci G, Wang L, Horne D, Chen J, Yang Y, Rosen ST. 8-Cl-Ado and 8-NH 2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia. Leukemia 2024; 38:1236-1245. [PMID: 38643304 PMCID: PMC11147765 DOI: 10.1038/s41375-024-02222-w] [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: 09/12/2023] [Revised: 02/29/2024] [Accepted: 03/06/2024] [Indexed: 04/22/2024]
Abstract
Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.
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Affiliation(s)
- Jiamin Guo
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA.
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.
| | - Ralf Buettner
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Li Du
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Wei Liu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Rui Su
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Zhenhua Chen
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Yuan Che
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Yi Zhang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Rui Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Le Xuan Truong Nguyen
- Department of Hematologic Malignancies Translational Science and Division of Leukemia, City of Hope, Duarte, CA, USA
| | - Roger E Moore
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
| | - Pathak Khyatiben
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Min-Hsuan Chen
- Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Pirrotte Patrick
- Integrated Mass Spectrometry Shared Resource, City of Hope, Duarte, CA, USA
- Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Guido Marcucci
- Department of Hematologic Malignancies Translational Science and Division of Leukemia, City of Hope, Duarte, CA, USA
| | - Lili Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - David Horne
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Jianjun Chen
- Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Yanzhong Yang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Steven T Rosen
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.
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12
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Ji M, Xu Q, Li X. Dietary methionine restriction in cancer development and antitumor immunity. Trends Endocrinol Metab 2024; 35:400-412. [PMID: 38383161 PMCID: PMC11096033 DOI: 10.1016/j.tem.2024.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 02/23/2024]
Abstract
Methionine restriction (MR) has been shown to suppress tumor growth and improve the responses to various anticancer therapies. However, methionine itself is required for the proliferation, activation, and differentiation of T cells that are crucial for antitumor immunity. The dual impact of methionine, that influences both tumor and immune cells, has generated concerns regarding the potential consequences of MR on T cell immunity and its possible role in promoting cancer. In this review we systemically examine current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings on MR in immunocompetent animals, we further discuss how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to MR.
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Affiliation(s)
- Ming Ji
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Qing Xu
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Xiaoling Li
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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13
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Zhang C, Du Z, Gao Y, Lim KS, Zhou W, Huang H, He H, Xiao J, Xu D, Li Q. Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma. Cell Metab 2024; 36:778-792.e10. [PMID: 38378000 DOI: 10.1016/j.cmet.2024.01.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 11/16/2023] [Accepted: 01/29/2024] [Indexed: 02/22/2024]
Abstract
Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-β) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-β+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-β+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.
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Affiliation(s)
- ChuanJie Zhang
- Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - ZunGuo Du
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; Department of Pathology, HuaShan Hospital, Fudan University, Shanghai 200040, China
| | - Yi Gao
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kiat Shenq Lim
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - WenJie Zhou
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hai Huang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - HongChao He
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Xiao
- Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China
| | - DanFeng Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - QingQuan Li
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
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14
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Liu CC, Chen L, Cai YW, Chen YF, Liu YM, Zhou YJ, Shao ZM, Yu KD. Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer. Cell Rep Med 2024; 5:101396. [PMID: 38290515 PMCID: PMC10897545 DOI: 10.1016/j.xcrm.2024.101396] [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: 05/26/2023] [Revised: 10/19/2023] [Accepted: 01/05/2024] [Indexed: 02/01/2024]
Abstract
Cancer stem cells (CSCs) are the most intractable subpopulation of triple-negative breast cancer (TNBC) cells, which have been associated with a high risk of relapse and poor prognosis. However, eradication of CSCs continues to be difficult. Here, we integrate the multiomics data of a TNBC cohort (n = 360) to identify vital markers of CSCs. We discover that EMSY, inducing a BRCAness phenotype, is preferentially expressed in breast CSCs, promotes ALDH+ cells enrichment, and is positively correlated with poor relapse-free survival. Mechanistically, EMSY competitively binds to the Jmjc domain, which is critical for KDM5B enzyme activity, to reshape methionine metabolism, and to promote CSC self-renewal and tumorigenesis in an H3K4 methylation-dependent manner. Moreover, EMSY accumulation in TNBC cells sensitizes them to PARP inhibitors against bulk cells and methionine deprivation against CSCs. These findings indicate that clinically relevant eradication of CSCs could be achieved with a strategy that targets CSC-specific vulnerabilities in amino acid metabolism.
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Affiliation(s)
- Cui-Cui Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Lie Chen
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yu-Wen Cai
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yu-Fei Chen
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yi-Ming Liu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yu-Jie Zhou
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Ke-Da Yu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
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15
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Garg S, Morehead LC, Bird JT, Graw S, Gies A, Storey AJ, Tackett AJ, Edmondson RD, Mackintosh SG, Byrum SD, Miousse IR. Characterization of methionine dependence in melanoma cells. Mol Omics 2024; 20:37-47. [PMID: 37782107 PMCID: PMC10903584 DOI: 10.1039/d3mo00087g] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood. We do know that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of S-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but triggers different outcomes in methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and immune functions in the cellular response to methionine stress in melanoma.
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Affiliation(s)
- Sarita Garg
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Lauren C Morehead
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Jordan T Bird
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Stefan Graw
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Allen Gies
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Aaron J Storey
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Rick D Edmondson
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Samuel G Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Stephanie D Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| | - Isabelle R Miousse
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
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16
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Bel’skaya LV, Gundyrev IA, Solomatin DV. The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review. Curr Issues Mol Biol 2023; 45:7513-7537. [PMID: 37754258 PMCID: PMC10527988 DOI: 10.3390/cimb45090474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/05/2023] [Accepted: 09/12/2023] [Indexed: 09/28/2023] Open
Abstract
This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10-15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer. The variability in the amino acid composition of biological fluids was shown to depend on the breast cancer phenotype, as well as the age, race, and menopausal status of patients. In general, the analysis of changes in the amino acid metabolism in breast cancer is a promising strategy not only for diagnosis, but also for developing new therapeutic agents, monitoring the treatment process, correcting complications after treatment, and evaluating survival rates.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
| | - Ivan A. Gundyrev
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
| | - Denis V. Solomatin
- Department of Mathematics and Mathematics Teaching Methods, Omsk State Pedagogical University, 644043 Omsk, Russia;
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17
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Yang C, Ou Y, Zhou Q, Liang Y, Li W, Chen Y, Chen W, Wu S, Chen Y, Dai X, Chen X, Chen T, Jin S, Liu Y, Zhang L, Liu S, Hu Y, Zou L, Mao S, Jiang H. Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment. Cell Death Dis 2023; 14:525. [PMID: 37582769 PMCID: PMC10427658 DOI: 10.1038/s41419-023-06050-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/19/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.
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Affiliation(s)
- Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Quan Zhou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yingchun Liang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Weijian Li
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Wensun Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Siqi Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yifan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Xiyu Dai
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Tian Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Shengming Jin
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yufei Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Limin Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Shenghua Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yun Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Lujia Zou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
| | - Shanhua Mao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
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18
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Xiao Y, Yu TJ, Xu Y, Ding R, Wang YP, Jiang YZ, Shao ZM. Emerging therapies in cancer metabolism. Cell Metab 2023; 35:1283-1303. [PMID: 37557070 DOI: 10.1016/j.cmet.2023.07.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 06/20/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023]
Abstract
Metabolic reprogramming in cancer is not only a biological hallmark but also reveals treatment vulnerabilities. Numerous metabolic molecules have shown promise as treatment targets to impede tumor progression in preclinical studies, with some advancing to clinical trials. However, the intricacy and adaptability of metabolic networks hinder the effectiveness of metabolic therapies. This review summarizes the metabolic targets for cancer treatment and provides an overview of the current status of clinical trials targeting cancer metabolism. Additionally, we decipher crucial factors that limit the efficacy of metabolism-based therapies and propose future directions. With advances in integrating multi-omics, single-cell, and spatial technologies, as well as the ability to track metabolic adaptation more precisely and dynamically, clinicians can personalize metabolic therapies for improved cancer treatment.
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Affiliation(s)
- Yi Xiao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Tian-Jian Yu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ying Xu
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Rui Ding
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Yi-Ping Wang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Yi-Zhou Jiang
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Zhi-Ming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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19
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Davies A, Zoubeidi A, Beltran H, Selth LA. The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity. Cancer Discov 2023; 13:1771-1788. [PMID: 37470668 PMCID: PMC10527883 DOI: 10.1158/2159-8290.cd-23-0225] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 06/09/2023] [Indexed: 07/21/2023]
Abstract
Lineage plasticity, a process whereby cells change their phenotype to take on a different molecular and/or histologic identity, is a key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage plasticity, it is predominantly a dynamic process controlled by transcriptional and epigenetic dysregulation. This review explores the transcriptional and epigenetic regulators of lineage plasticity and their interplay with other features of malignancy, such as dysregulated metabolism, the tumor microenvironment, and immune evasion. We also discuss strategies for the detection and treatment of highly plastic tumors. SIGNIFICANCE Lineage plasticity is a hallmark of cancer and a critical facilitator of other oncogenic features such as metastasis, therapy resistance, dysregulated metabolism, and immune evasion. It is essential that the molecular mechanisms of lineage plasticity are elucidated to enable the development of strategies to effectively target this phenomenon. In this review, we describe key transcriptional and epigenetic regulators of cancer cell plasticity, in the process highlighting therapeutic approaches that may be harnessed for patient benefit.
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Affiliation(s)
- Alastair Davies
- Oncology Research Discovery, Pfizer Worldwide Research and Development, San Diego, CA, USA
| | - Amina Zoubeidi
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Himisha Beltran
- Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Luke A. Selth
- Flinders Health and Medical Research Institute and Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, South Australia, 5042 Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5005 Australia
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20
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Fan M, Shi Y, Zhao J, Li L. Cancer stem cell fate determination: mito-nuclear communication. Cell Commun Signal 2023; 21:159. [PMID: 37370081 PMCID: PMC10294499 DOI: 10.1186/s12964-023-01160-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/06/2023] [Indexed: 06/29/2023] Open
Abstract
Cancer stem cells (CSCs) are considered to be responsible for tumor recurrence and metastasis. Therefore, clarification of the mechanisms involved in CSC stemness maintenance and cell fate determination would provide a new strategy for cancer therapy. Unregulated cellular energetics has been accepted as one of the hallmarks of cancer cells, but recent studies have revealed that mitochondrial metabolism can also actively determine CSC fate by affecting nuclear stemness gene expression. Herein, from the perspective of mito-nuclear communication, we review recent progress on the influence of mitochondria on CSC potential from four aspects: metabolism, dynamics, mitochondrial homeostasis, and reactive oxygen species (ROS). Video Abstract.
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Affiliation(s)
- Mengchen Fan
- School of Basic Medical Sciences, Medical College of Yan’an University, Yanan, 716000 China
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, 710032 China
| | - Ying Shi
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, 710032 China
| | - Jumei Zhao
- School of Basic Medical Sciences, Medical College of Yan’an University, Yanan, 716000 China
| | - Ling Li
- Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, 710032 China
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21
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Garg S, Morehead LC, Bird JT, Graw S, Gies A, Storey AJ, Tackett AJ, Edmondson RD, Mackintosh SG, Byrum SD, Miousse IR. Characterization of methionine dependence in melanoma cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.05.535723. [PMID: 37066392 PMCID: PMC10104025 DOI: 10.1101/2023.04.05.535723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood. We do know that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but triggers different outcomes in methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and immune functions in the cellular response to methionine stress in melanoma.
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Affiliation(s)
- Sarita Garg
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Lauren C Morehead
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Jordan T Bird
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Stefan Graw
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Allen Gies
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Aaron J Storey
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Rick D Edmondson
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Samuel G Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Stephanie D Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
| | - Isabelle R Miousse
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences
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22
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Kavya D, Nadumane VK. A combination of semi-purified L-methioninase with tamoxifen citrate to ameliorate breast cancer in athymic nude mice. Mol Biol Rep 2023; 50:2925-2932. [PMID: 36566301 DOI: 10.1007/s11033-022-08144-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 11/22/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND Chemotherapy nonspecifically targets both tumor and healthy proliferating cells. Methionine deprivation using L-methioninase along with chemotherapy appears promising towards cancer management. The present study is an attempt to use a new combination of L-methioninase with Tamoxifen (TAM) to treat breast cancer in mice. METHODS AND RESULTS L-Methioninase from Methylobacterium sp. was partially purified (SPMet's) by cold acetone precipitation and lyophilized. Its cytotoxicity effect, alone and in combination with Tamoxifen, was evaluated in vitro (MCF-7) cells and in vivo (athymic nude mice) conditions. SPMet's was found to inhibit the growth of MCF-7 cells with an IC50 value of 47.05 µg/ml, while the combination of SPMet's and TAM had an IC50 of 6.4 µg/ml. Athymic nude mice were grouped into: Group-I - Tumor control; Group-II - TAM; Group-III - SPMet's; Group-IV - SPMet's + TAM. Tumor growth inhibition (TGI) was maximum in Group-IV with 84.65% followed by Group-II with 65.12%. Hematological and Biochemical parameters in Group-II, III, and IV were restored to normal levels. Tumor histopathology showed increased apoptosis and necrosis in Group-IV. Caspases 3 & 8 gene upregulation was significantly higher in Group-IV than other treated groups, indicating higher efficacy of the combination approach. CONCLUSION This is the first study report about a combination of SPMet's and TAM on in vivo breast cancer model, with significantly higher anticancer activity and without noticeable side effects. The findings of this study have several important implications for future clinical studies.
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Affiliation(s)
- D Kavya
- Department of Biotechnology, School of Sciences, Jain Deemed-to-be-University, Bangalore, Karnataka, India
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23
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Zhang Z, Bao C, Jiang L, Wang S, Wang K, Lu C, Fang H. When cancer drug resistance meets metabolomics (bulk, single-cell and/or spatial): Progress, potential, and perspective. Front Oncol 2023; 12:1054233. [PMID: 36686803 PMCID: PMC9854130 DOI: 10.3389/fonc.2022.1054233] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/20/2022] [Indexed: 01/07/2023] Open
Abstract
Resistance to drug treatment is a critical barrier in cancer therapy. There is an unmet need to explore cancer hallmarks that can be targeted to overcome this resistance for therapeutic gain. Over time, metabolic reprogramming has been recognised as one hallmark that can be used to prevent therapeutic resistance. With the advent of metabolomics, targeting metabolic alterations in cancer cells and host patients represents an emerging therapeutic strategy for overcoming cancer drug resistance. Driven by technological and methodological advances in mass spectrometry imaging, spatial metabolomics involves the profiling of all the metabolites (metabolomics) so that the spatial information is captured bona fide within the sample. Spatial metabolomics offers an opportunity to demonstrate the drug-resistant tumor profile with metabolic heterogeneity, and also poses a data-mining challenge to reveal meaningful insights from high-dimensional spatial information. In this review, we discuss the latest progress, with the focus on currently available bulk, single-cell and spatial metabolomics technologies and their successful applications in pre-clinical and translational studies on cancer drug resistance. We provide a summary of metabolic mechanisms underlying cancer drug resistance from different aspects; these include the Warburg effect, altered amino acid/lipid/drug metabolism, generation of drug-resistant cancer stem cells, and immunosuppressive metabolism. Furthermore, we propose solutions describing how to overcome cancer drug resistance; these include early detection during cancer initiation, monitoring of clinical drug response, novel anticancer drug and target metabolism, immunotherapy, and the emergence of spatial metabolomics. We conclude by describing the perspectives on how spatial omics approaches (integrating spatial metabolomics) could be further developed to improve the management of drug resistance in cancer patients.
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Affiliation(s)
- Zhiqiang Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Chaohui Bao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Jiang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shan Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kankan Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang Lu
- MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
| | - Hai Fang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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24
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Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players. Cells 2022; 11:cells11223607. [PMID: 36429035 PMCID: PMC9688847 DOI: 10.3390/cells11223607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/09/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through its role in the endogenous synthesis of methionine and S-adenosylmethionine (SAM), the universal donor of methyl groups in eukaryotic cells. OCM genes are differentially expressed in stem cells, compared to their differentiated counterparts. Furthermore, cultivating stem cells in methionine-restricted conditions hinders their stemness capacities through decreased SAM levels with a subsequent decrease in histone methylation, notably H3K4me3, with a decrease in stem cell markers. Stem cells' reliance on methionine is linked to several mechanisms, including high methionine flux or low endogenous methionine biosynthesis. In this review, we provide an overview of the recent discoveries concerning this metabolic dependence and we discuss the mechanisms behind them. We highlight the influence of SIRT1 on SAM synthesis and suggest a role of PGC-1α/PPAR-α in impaired stemness produced by methionine deprivation. In addition, we discuss the potential interest of methionine restriction in regenerative medicine and cancer treatment.
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25
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Yang PW, Jiao JY, Chen Z, Zhu XY, Cheng CS. Keep a watchful eye on methionine adenosyltransferases, novel therapeutic opportunities for hepatobiliary and pancreatic tumours. Biochim Biophys Acta Rev Cancer 2022; 1877:188793. [PMID: 36089205 DOI: 10.1016/j.bbcan.2022.188793] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/31/2022] [Accepted: 08/30/2022] [Indexed: 11/18/2022]
Abstract
Methionine adenosyltransferases (MATs) synthesize S-adenosylmethionine (SAM) from methionine, which provides methyl groups for DNA, RNA, protein, and lipid methylation. MATs play a critical role in cellular processes, including growth, proliferation, and differentiation, and have been implicated in tumour development and progression. The expression of MATs is altered in hepatobiliary and pancreatic (HBP) cancers, which serves as a rare biomarker for early diagnosis and prognosis prediction of HBP cancers. Independent of SAM depletion in cells, MATs are often dysregulated at the transcriptional, post-transcriptional, and post-translational levels. Dysregulation of MATs is involved in carcinogenesis, chemotherapy resistance, T cell exhaustion, activation of tumour-associated macrophages, cancer stemness, and activation of tumourigenic pathways. Targeting MATs both directly and indirectly is a potential therapeutic strategy. This review summarizes the dysregulations of MATs, their proposed mechanism, diagnostic and prognostic roles, and potential therapeutic effects in context of HBP cancers.
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Affiliation(s)
- Pei-Wen Yang
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ju-Ying Jiao
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Zhen Chen
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiao-Yan Zhu
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Chien-Shan Cheng
- Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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26
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Guo J, Yang Y, Buettner R, Rosen ST. Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy. Curr Opin Oncol 2022; 34:546-551. [PMID: 35788128 PMCID: PMC9365249 DOI: 10.1097/cco.0000000000000870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW In this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S -adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionine-MAT2A-SAM axis will be discussed. RECENT FINDINGS SAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer. SUMMARY The methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.
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Affiliation(s)
- Jiamin Guo
- Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California
- Irell & Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, California
| | - Yanzhong Yang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope National Cancer Center, Duarte, California
| | - Ralf Buettner
- Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California
| | - Steven T. Rosen
- Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California
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27
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Li C, Gui G, Zhang L, Qin A, Zhou C, Zha X. Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. J Med Chem 2022; 65:9531-9547. [PMID: 35796517 DOI: 10.1021/acs.jmedchem.2c00395] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Methionine adenosyltransferase 2A (MAT2A) is a rate-limiting enzyme in the methionine cycle that primarily catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). MAT2A has been recognized as a therapeutic target for the treatment of cancers. Recently, a few MAT2A inhibitors have been reported, and three entered clinical trials to treat solid tumorsor lymphoma with MTAP loss. This review aims to summarize the current understanding of the roles of MAT2A in cancer and the discovery of MAT2A inhibitors. Furthermore, a perspective on the use of MAT2A inhibitors for the treatment of cancer is also discussed. We hope to provide guidance for future drug design and optimization via analysis of the binding modes of known MAT2A inhibitors.
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Affiliation(s)
- Chunzheng Li
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Gang Gui
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Li Zhang
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Anqi Qin
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Chen Zhou
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States
| | - Xiaoming Zha
- Department of Pharmaceutical Engineering, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
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28
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Sedillo JC, Cryns VL. Targeting the methionine addiction of cancer. Am J Cancer Res 2022; 12:2249-2276. [PMID: 35693095 PMCID: PMC9185618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/14/2022] [Indexed: 06/15/2023] Open
Abstract
Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.
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Affiliation(s)
- Joni C Sedillo
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health Madison, WI, USA
| | - Vincent L Cryns
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health Madison, WI, USA
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29
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Golbourn BJ, Halbert ME, Halligan K, Varadharajan S, Krug B, Mbah NE, Kabir N, Stanton ACJ, Locke AL, Casillo SM, Zhao Y, Sanders LM, Cheney A, Mullett SJ, Chen A, Wassell M, Andren A, Perez J, Jane EP, Premkumar DRD, Koncar RF, Mirhadi S, McCarl LH, Chang YF, Wu YL, Gatesman TA, Cruz AF, Zapotocky M, Hu B, Kohanbash G, Wang X, Vartanian A, Moran MF, Lieberman F, Amankulor NM, Wendell SG, Vaske OM, Panigrahy A, Felker J, Bertrand KC, Kleinman CL, Rich JN, Friedlander RM, Broniscer A, Lyssiotis C, Jabado N, Pollack IF, Mack SC, Agnihotri S. Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome. NATURE CANCER 2022; 3:629-648. [PMID: 35422502 PMCID: PMC9551679 DOI: 10.1038/s43018-022-00348-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/18/2022] [Indexed: 12/31/2022]
Abstract
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
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Affiliation(s)
- Brian J Golbourn
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Matthew E Halbert
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Katharine Halligan
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pediatrics, Division of Hematology-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Srinidhi Varadharajan
- Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA
| | - Brian Krug
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Nneka E Mbah
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nisha Kabir
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Ann-Catherine J Stanton
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Abigail L Locke
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Stephanie M Casillo
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Yanhua Zhao
- Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA
| | - Lauren M Sanders
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA
| | - Allison Cheney
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA
- University of California Santa Cruz Genomics Institute, Santa Cruz, CA, USA
| | - Steven J Mullett
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Apeng Chen
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, PR China
| | - Michelle Wassell
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Anthony Andren
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jennifer Perez
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Esther P Jane
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Daniel R David Premkumar
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert F Koncar
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Shideh Mirhadi
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Lauren H McCarl
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Yue-Fang Chang
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yijen L Wu
- Department of Developmental Biology, University of Pittsburgh and Rangos Research Center Animal Imaging Core, Pittsburgh, PA, USA
| | - Taylor A Gatesman
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Andrea F Cruz
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Michal Zapotocky
- Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Baoli Hu
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Gary Kohanbash
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Xiuxing Wang
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | | | - Michael F Moran
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Frank Lieberman
- Department of Neurology, Adult Neurooncology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Nduka M Amankulor
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Stacy G Wendell
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Olena M Vaske
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA
- University of California Santa Cruz Genomics Institute, Santa Cruz, CA, USA
| | - Ashok Panigrahy
- Department of Radiology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - James Felker
- Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kelsey C Bertrand
- Department of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Claudia L Kleinman
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Jeremy N Rich
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Robert M Friedlander
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Alberto Broniscer
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- Pediatrics, Division of Hematology-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Costas Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada
| | - Ian F Pollack
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Stephen C Mack
- Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA.
- Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
| | - Sameer Agnihotri
- Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
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30
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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31
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Liu C, Wang JL, Wu DZ, Yuan YW, Xin L. Methionine restriction enhances the chemotherapeutic sensitivity of colorectal cancer stem cells by miR-320d/c-Myc axis. Mol Cell Biochem 2022; 477:2001-2013. [PMID: 35394639 DOI: 10.1007/s11010-022-04416-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 03/16/2022] [Indexed: 11/25/2022]
Abstract
Chemotherapy resistance of colorectal cancer stem cells (CRC-SCs) has become a major challenge in clinical treatment of cancer. Methionine restriction (MR) enhances the therapeutic effect of chemotherapeutic agents. The aim of this study was to explore the molecular pathways that MR affects the chemotherapeutic sensitivity of CRC-SCs. CD133+ and CD133- SW480 or SW620 cells were isolated by magnetic-activated cell sorting (MACS). Mouse xenograft tumor model was established by subcutaneous inoculation of CD133+ SW480. MTT assay was used to detect cell viability. Phase distribution of cell cycle was detected by flow cytometry. Western blotting was used to detect drug-resistant related protein expression. miR-320d and transcription factor c-Myc expressions were detected by qRT-PCR. The interaction between miR-320d and c-Myc was verified by luciferase assay. CD133+ SW480 and SW620 cells were more resistant to 5-fluorouracil (5-FU) than CD133- cells. In vitro and in vivo experiments showed that 5-FU and MR combined therapy further inhibited CD133+ cell activity and ATP binding cassette subfamily G member 2 (ABCG2) expression, and reduced tumor volume compared with drug administration alone. Interference with miR-320d or overexpression of c-Myc reversed the increased chemotherapeutic sensitivity of CRC-SCs induced by synergistic therapy with 5-FU and MR. miR-320d can target and regulate c-Myc. Interference with c-Myc could reverse the increase in cell viability and ABCG2 expression caused by down-regulation of miR-320d. In conclusion, the combined chemotherapy with MR can enhance the chemotherapeutic sensitivity of CRC-SCs by up-regulation of miR-320d to inhibit c-Myc expression, which lays a molecular basis for MR regulation of chemotherapeutic sensitivity of CRC-SCs.
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Affiliation(s)
- Chuan Liu
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jin-Liang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Deng-Zhong Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Yi-Wu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China
| | - Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, 330006, Jiangxi Province, China.
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32
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Essential amino acids deprivation is a potential strategy for breast cancer treatment. Breast 2022; 62:152-161. [PMID: 35217381 PMCID: PMC8873954 DOI: 10.1016/j.breast.2022.02.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 11/23/2022] Open
Abstract
Aims The study aimed to search novel, simple and practical index reflecting the level of essential amino acids (EAAs) metabolism in breast cancer (BC), as well as to explore the effect of enhanced EAAs metabolism on the prognosis and immune microenvironment of BC, thus providing new evidence for the application of EAAs deprivation in the BC treatment. Methods The study includes the analysis of multi-omics and clinical data of 13 BC cell lines and 2898 BC patients in the public database. Further validation was performed using multi-omics and immunohistochemistry data from 83 BC tissue samples collected at our hospital. Results According to the multi-omics data, the SLC7A5 to SLC7A8 Ratio (SSR) score was found to be significantly correlated with the EAAs level and EAAs-metabolic activity of BC, suggesting that the SSR score might be used as a biomarker to assess the degree of EAAs metabolism in BC. Besides, BC patients with high EAAs metabolism had shorter overall survival (OS) time, higher PD-L1 expression, and higher T regulatory cells (Tregs) infiltration, indicating that a high EAAs metabolism was related to a poor prognosis and immune suppression in BC. Additionally, MYC amplification is a critical molecular process in the metabolic reprogramming of EAAs in BC. Conclusion EAAs may be a possible therapeutic target for BC treatment.
A novel biomarker to assess the EAAs metabolism in breast cancer. High EAAs metabolism is related to a poor prognosis in breast cancer. High EAAs metabolism is also related to immune suppression in breast cancer. MYC amplification drives the metabolic reprogramming of EAAs in breast cancer.
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Oxidative Stress Aggravates Apoptosis of Nucleus Pulposus Cells through m 6A Modification of MAT2A Pre-mRNA by METTL16. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4036274. [PMID: 35069973 PMCID: PMC8767407 DOI: 10.1155/2022/4036274] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/18/2021] [Accepted: 12/07/2021] [Indexed: 12/22/2022]
Abstract
The process of intervertebral disc degeneration (IVDD) is complex, and its mechanism is considered multifactorial. Apoptosis of oxidative stressed nucleus pulposus cells (NPCs) should be a fundamental element in the pathogenesis of IVDD. In our pilot study, we found that the expression of MAT2A decreased, and METTL16 increased in the degenerative nucleus pulposus tissues. Previous studies have shown that the balance of splicing, maturation, and degradation of MAT2A pre-mRNA is regulated by METTL16 m6A modification. In the current study, we aimed to figure out whether this mechanism was involved in the aberrant apoptosis of NPCs and IVDD. Human NPCs were isolated and cultured under oxidative stress. An IVDD animal model was established. It showed that significantly higher METTL16 expression and lower MAT2A expression were seen in either the NPCs under oxidative stress or the degenerative discs of the animal model. MAT2A was inhibited with siRNA in vitro or cycloleucine in vivo. METTL16 was overexpressed with lentivirus in vitro or in vivo. Downregulation of MAT2A or upregulation of METTL16 aggravated nucleus pulposus cell apoptosis and disc disorganization. The balance of splicing, maturation, and degradation of MAT2A pre-mRNA was significantly inclined to degradation in the NPCs with the overexpression of METTL16. Increased apoptosis of NPCs under oxidative stress could be rescued by reducing the expression of METTL16 using siRNA with more maturation of MAT2A pre-mRNA. Collectively, oxidative stress aggravates apoptosis of NPCs through disrupting the balance of splicing, maturation, and degradation of MAT2A pre-mRNA, which is m6A modified by METTL16.
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34
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Hajjaji N, Aboulouard S, Cardon T, Bertin D, Robin YM, Fournier I, Salzet M. Path to Clonal Theranostics in Luminal Breast Cancers. Front Oncol 2022; 11:802177. [PMID: 35096604 PMCID: PMC8793283 DOI: 10.3389/fonc.2021.802177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022] Open
Abstract
Integrating tumor heterogeneity in the drug discovery process is a key challenge to tackle breast cancer resistance. Identifying protein targets for functionally distinct tumor clones is particularly important to tailor therapy to the heterogeneous tumor subpopulations and achieve clonal theranostics. For this purpose, we performed an unsupervised, label-free, spatially resolved shotgun proteomics guided by MALDI mass spectrometry imaging (MSI) on 124 selected tumor clonal areas from early luminal breast cancers, tumor stroma, and breast cancer metastases. 2868 proteins were identified. The main protein classes found in the clonal proteome dataset were enzymes, cytoskeletal proteins, membrane-traffic, translational or scaffold proteins, or transporters. As a comparison, gene-specific transcriptional regulators, chromatin related proteins or transmembrane signal receptor were more abundant in the TCGA dataset. Moreover, 26 mutated proteins have been identified. Similarly, expanding the search to alternative proteins databases retrieved 126 alternative proteins in the clonal proteome dataset. Most of these alternative proteins were coded mainly from non-coding RNA. To fully understand the molecular information brought by our approach and its relevance to drug target discovery, the clonal proteomic dataset was further compared to the TCGA breast cancer database and two transcriptomic panels, BC360 (nanoString®) and CDx (Foundation One®). We retrieved 139 pathways in the clonal proteome dataset. Only 55% of these pathways were also present in the TCGA dataset, 68% in BC360 and 50% in CDx. Seven of these pathways have been suggested as candidate for drug targeting, 22 have been associated with breast cancer in experimental or clinical reports, the remaining 19 pathways have been understudied in breast cancer. Among the anticancer drugs, 35 drugs matched uniquely with the clonal proteome dataset, with only 7 of them already approved in breast cancer. The number of target and drug interactions with non-anticancer drugs (such as agents targeting the cardiovascular system, metabolism, the musculoskeletal or the nervous systems) was higher in the clonal proteome dataset (540 interactions) compared to TCGA (83 interactions), BC360 (419 interactions), or CDx (172 interactions). Many of the protein targets identified and drugs screened were clinically relevant to breast cancer and are in clinical trials. Thus, we described the non-redundant knowledge brought by this clone-tailored approach compared to TCGA or transcriptomic panels, the targetable proteins identified in the clonal proteome dataset, and the potential of this approach for drug discovery and repurposing through drug interactions with antineoplastic agents and non-anticancer drugs.
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Affiliation(s)
- Nawale Hajjaji
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.,Breast Cancer Unit, Oscar Lambret Center, Lille, France
| | - Soulaimane Aboulouard
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France
| | - Tristan Cardon
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France
| | - Delphine Bertin
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.,Breast Cancer Unit, Oscar Lambret Center, Lille, France
| | - Yves-Marie Robin
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.,Breast Cancer Unit, Oscar Lambret Center, Lille, France
| | - Isabelle Fournier
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.,Institut universitaire de France, Paris, France
| | - Michel Salzet
- Univ. Lille, Inserm, CHU Lille, U1192, Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Lille, France.,Institut universitaire de France, Paris, France
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35
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Amino Acid Metabolism in Cancer Drug Resistance. Cells 2022; 11:cells11010140. [PMID: 35011702 PMCID: PMC8750102 DOI: 10.3390/cells11010140] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
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36
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Xin L, Lu H, Liu C, Zeng F, Yuan YW, Wu Y, Wang JL, Wu DZ, Zhou LQ. Methionine deficiency promoted mitophagy via lncRNA PVT1-mediated promoter demethylation of BNIP3 in gastric cancer. Int J Biochem Cell Biol 2021; 141:106100. [PMID: 34678458 DOI: 10.1016/j.biocel.2021.106100] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND The occurrence of recurrence and metastasis after treatment is a major challenge in the treatment of gastric cancer. This study was based on the methionine (Met)-dependent characteristics of gastric cancer cells to explore the effect of Met deficiency on the occurrence and development of gastric cancer. METHODS Human gastric cancer cell lines MKN45 and AGS and nude mice model were used to explore how Met affects gastric cancer by regulating lncRNA PVT1. RESULTS The levels of lncRNA PVT1 in gastric cancer cells and human gastric cancer xenografts of nude mice were down-regulated under the condition of Met deficiency. The cell viability and cell proliferation were declined after MKN45 and SGC-790 cells were cultured in Met-deficient medium. LncRNA PVT1 could affect BNIP3 promoter DNA methylation level through its interaction with DNMT1. Moreover, the silence of lncRNA PVT1 and the up-regulation of BNIP3 level inhibited the gastric cancer cell proliferation. Met deficiency could up-regulate BNIP3 expression by inhibiting the binding of lncRNA PVT1 to DNMT1, and activate mitophagy, thus inhibiting gastric cancer cell proliferation. CONCLUSION Our study suggested that Met deficiency could down-regulate the expression of lncRNA PVT1, further demethylated the promoter of BNIP3, thus inhibiting the proliferation of gastric cancer cells by activating mitophagy.
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Affiliation(s)
- Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
| | - Hao Lu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Chuan Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Fei Zeng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yi-Wu Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - You Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jin-Liang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Deng-Zhong Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Li-Qiang Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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37
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Altundag Ö, Canpinar H, Çelebi-Saltik B. Methionine affects the expression of pluripotency genes and protein levels associated with methionine metabolism in adult, fetal, and cancer stem cells. J Cell Biochem 2021; 123:406-416. [PMID: 34783058 DOI: 10.1002/jcb.30180] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/01/2021] [Accepted: 11/05/2021] [Indexed: 01/07/2023]
Abstract
Intracellular and extracellular regulatory factors promote the potency and self-renewal property of stem cells. Methionine is fundamental for protein synthesis and regulation of methylation reactions. Specifically, methionine metabolism in embryonic and fetal development processes regulates gene expression profile/epigenetic identity of stem cells to achieve pluripotency and cellular functions. We aimed to reveal the differences in methionine metabolism of bone marrow (BM)-mesenchymal stem cells (MSCs), umbilical cord blood (UCB)-MSCs, and cancer stem cells (CSCs), which reflect different metabolic profiles and developmental stages of stem cells. UCB-MSC, BM-MSCs, and breast CSCs were treated with different doses (0, 10, 25, 50, and 100 µM) of l-methionine. Cell surface marker and cell cycle assessment were performed by flow cytometry. Changes in gene expressions (OCT3/4, NANOG, DMNT1, DNMT3A, and DNMT3B, MAT2A, and MAT2B) with methionine supplementation were examined by quantitative real-time polymerase chain reaction and the changes in histone methylation (H3K4me3, H3K27me3) levels were demonstrated by western blot analysis. S-adenosylmethionine//S-adenosylhomocysteine (SAM/SAH) levels were evaluated by enzyme-linked immunosorbent assay. Cells that were exposed to different concentrations of l-methionine, were mostly arrested in the G0/G1 phase for each stem cell group. It was evaluated that BM-MSCs increased all gene expressions in the culture medium-containing 100 µM methionine, in addition to SAM/SAH levels. On the other hand, UCB-MSCs were found to increase OCT3/4, NANOG, and DNMT1 gene expressions and decrease MAT2A and MAT2B expressions in the culture medium containing 10 µM methionine. Moreover, an increase was observed in the He3K4me3 methylation profile. In addition, OCT3/4, NANOG, DNMT1, and MAT2B gene expressions in CSCs increased starting from the addition of 25 µM methionine. An increase was determined in H3K4me3 protein expression at 50 and 100 µM methionine-supplemented culture condition. This study demonstrates that methionine plays a critical role in metabolism and epigenetic regulation in different stem cell groups.
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Affiliation(s)
- Özlem Altundag
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Sihhiye, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Sihhiye, Turkey
| | - Hande Canpinar
- Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Sihhiye, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, Ankara, Sihhiye, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Sihhiye, Turkey
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38
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Malin D, Lee Y, Chepikova O, Strekalova E, Carlson A, Cryns VL. Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase. Breast Cancer Res Treat 2021; 190:373-387. [PMID: 34553295 DOI: 10.1007/s10549-021-06398-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 09/11/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE Tumor cells are dependent on the glutathione and thioredoxin antioxidant pathways to survive oxidative stress. Since the essential amino acid methionine is converted to glutathione, we hypothesized that methionine restriction (MR) would deplete glutathione and render tumors dependent on the thioredoxin pathway and its rate-limiting enzyme thioredoxin reductase (TXNRD). METHODS Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control or MR media and the effects on reactive oxygen species (ROS) and antioxidant signaling were examined. To determine the role of TXNRD in MR-induced cell death, TXNRD1 was inhibited by RNAi or the pan-TXNRD inhibitor auranofin, an antirheumatic agent. Metastatic and PDX TNBC mouse models were utilized to evaluate in vivo antitumor activity. RESULTS MR rapidly and transiently increased ROS, depleted glutathione, and decreased the ratio of reduced glutathione/oxidized glutathione in TNBC cells. TXNRD1 mRNA and protein levels were induced by MR via a ROS-dependent mechanism mediated by the transcriptional regulators NRF2 and ATF4. MR dramatically sensitized TNBC cells to TXNRD1 silencing and the TXNRD inhibitor auranofin, as determined by crystal violet staining and caspase activity; these effects were suppressed by the antioxidant N-acetylcysteine. H-Ras-transformed MCF-10A cells, but not untransformed MCF-10A cells, were highly sensitive to the combination of auranofin and MR. Furthermore, dietary MR induced TXNRD1 expression in mammary tumors and enhanced the antitumor effects of auranofin in metastatic and PDX TNBC murine models. CONCLUSION MR exposes a vulnerability of TNBC cells to the TXNRD inhibitor auranofin by increasing expression of its molecular target and creating a dependency on the thioredoxin pathway.
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Affiliation(s)
- Dmitry Malin
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Yoonkyu Lee
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Olga Chepikova
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.,Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Ave, 354340, Sochi, Russia
| | - Elena Strekalova
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Alexis Carlson
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA
| | - Vincent L Cryns
- Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
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39
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Wilder CS, Chen Z, DiGiovanni J. Pharmacologic approaches to amino acid depletion for cancer therapy. Mol Carcinog 2021; 61:127-152. [PMID: 34534385 DOI: 10.1002/mc.23349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 11/09/2022]
Abstract
Cancer cells undergo metabolic reprogramming to support increased demands in bioenergetics and biosynthesis and to maintain reactive oxygen species at optimum levels. As metabolic alterations are broadly observed across many cancer types, metabolic reprogramming is considered a hallmark of cancer. A metabolic alteration commonly seen in cancer cells is an increased demand for certain amino acids. Amino acids are involved in a wide range of cellular functions, including proliferation, redox balance, bioenergetic and biosynthesis support, and homeostatic functions. Thus, targeting amino acid dependency in cancer is an attractive strategy for a number of cancers. In particular, pharmacologically mediated amino acid depletion has been evaluated as a cancer treatment option for several cancers. Amino acids that have been investigated for the feasibility of drug-induced depletion in preclinical and clinical studies for cancer treatment include arginine, asparagine, cysteine, glutamine, lysine, and methionine. In this review, we will summarize the status of current research on pharmacologically mediated amino acid depletion as a strategy for cancer treatment and potential chemotherapeutic combinations that synergize with amino acid depletion to further inhibit tumor growth and progression.
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Affiliation(s)
- Carly S Wilder
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - Zhao Chen
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.,Center for Molecular Carcinogenesis and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA
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40
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Zhao Y, Pu C, Jiao D, Zhu J, Guo X, Liu Z. Essential amino acid metabolism-related molecular classification in triple-negative breast cancer. Epigenomics 2021; 13:1247-1268. [PMID: 34448400 DOI: 10.2217/epi-2021-0210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Aim: To develop an approach to characterize and classify triple-negative breast cancer (TNBC) tumors based upon their essential amino acid (EAA) metabolic activity. Methods: We performed bioinformatic analyses of genomic, transcriptomic and clinical data in an integrated cohort of 740 TNBC patients from public databases. Results: Based on EAA metabolism-related gene expression patterns, two TNBC subtypes were identified with distinct prognoses and genomic alterations. Patients exhibiting an upregulated EAA metabolism phenotype were more prone to chemoresistance but also expressed higher levels of immune checkpoint genes and may be better candidates for immune checkpoint inhibitor therapy. Conclusion: Metabolic classification based upon EAA profiles offers a novel biological insight into previously established TNBC subtypes and advances current understanding of TNBC's metabolic heterogeneity.
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Affiliation(s)
- Yajie Zhao
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Chunrui Pu
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Dechuang Jiao
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Jiujun Zhu
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Xuhui Guo
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Zhenzhen Liu
- Department of Breast, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China
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Qiao J, Zhao C. Therapeutic effect of adenosylmethionine on viral hepatitis and related factors inducing diseas. Am J Transl Res 2021; 13:9485-9494. [PMID: 34540070 PMCID: PMC8430085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/01/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE To analyze the therapeutic efficacy of adenosylmethionine on viral hepatitis and the related factors inducing disease. METHODS From May 2018 to April 2019, 137 patients with viral hepatitis who received treatment in our hospital were selected and assigned to two groups according to different treatment methods. In the control group (CG), 61 cases were treated with routine liver protection and enzyme reduction. In the research group, 76 cases were treated with adenosylmethionine on the basis of the CG. After therapy, the total response rate was analyzed in both groups, and the adverse reactions were observed during the treatment. The liver function indexes [albumin (ALB), alanine aminotransferase (ALT), glutamic acid transaminase (AST) and total bilirubin (TBIL)], liver fiber indicators [hyaluronic acid (HA), laminin (LN), type III procollagen (PCIII), type IV collagen (IV-C)], inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)] were compared in both groups before and after therapy. ELISA was applied to detect inflammatory factors in both groups before and after treatment. Logistic analysis was applied to analyze the independent risk factors affecting the curative effect of patients with viral hepatitis. RESULTS After therapy, the total response rate of patients in RG was obviously higher than that in CG; The total incidence of adverse effects in RG was obviously lower than that in CG; The improvement of liver function indexes and liver fiber indicators in RG was better than that in CG; The expression of inflammatory factors in RG was obviously lower than that in CG. Logistic analysis revealed that patients' age (>40 years old), drinking history, family history, low improvement of hepatic function and hepatic fibrosis, high level of inflammatory cytokines and routine treatment were independent prognostic factors affecting patients with viral hepatitis. CONCLUSION Adenosylmethionine intervention can promote disease recovery, reduce inflammation level and improve liver function damage for patients with viral hepatitis.
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Affiliation(s)
- Jinggui Qiao
- Department of Gastroenterology, Xi'an Gaoxing Hospital Xi'an 710000, Shaanxi Province, China
| | - Congya Zhao
- Department of Gastroenterology, Xi'an Gaoxing Hospital Xi'an 710000, Shaanxi Province, China
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Circ_0044516 Regulates miR-136/MAT2A Pathway to Facilitate Lung Cancer Development. J Immunol Res 2021; 2021:5510869. [PMID: 34258296 PMCID: PMC8253637 DOI: 10.1155/2021/5510869] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/05/2021] [Accepted: 06/04/2021] [Indexed: 01/22/2023] Open
Abstract
Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.
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MAT2A Localization and Its Independently Prognostic Relevance in Breast Cancer Patients. Int J Mol Sci 2021; 22:ijms22105382. [PMID: 34065390 PMCID: PMC8161225 DOI: 10.3390/ijms22105382] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/02/2021] [Accepted: 05/13/2021] [Indexed: 02/07/2023] Open
Abstract
(1) Background: methionine cycle is not only essential for cancer cell proliferation but is also critical for metabolic reprogramming, a cancer hallmark. Hepatic and extrahepatic tissues methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A that catalyze the formation of S-adenosylmethionine (SAM), the principal biological methyl donor. Glycine N-methyltransferase (GNMT) further utilizes SAM for sarcosine formation, thus it regulates the ratio of SAM:S-adenosylhomocysteine (SAH). (2) Methods: by analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that breast cancer patients with higher MAT2A had worse survival rate (p = 0.0057). Protein expression pattern of MAT1AA, MAT2A and GNMT were investigated in the tissue microarray in our own cohort (n = 252) by immunohistochemistry. MAT2A C/N expression ratio and cell invasion activity were further investigated in a panel of breast cancer cell lines. (3) Results: GNMT and MAT1A were detected in the cytoplasm, whereas MAT2A showed both cytoplasmic and nuclear immunoreactivity. Neither GNMT nor MAT1A protein expression was associated with patient survival rate in our cohort. Kaplan–Meier survival curves showed that a higher cytoplasmic/nuclear (C/N) MAT2A protein expression ratio correlated with poor overall survival (5 year survival rate: 93.7% vs. 83.3%, C/N ratio ≥ 1.0 vs. C/N ratio < 1.0, log-rank p = 0.004). Accordingly, a MAT2A C/N expression ratio ≥ 1.0 was determined as an independent risk factor by Cox regression analysis (hazard ratio = 2.771, p = 0.018, n = 252). In vitro studies found that breast cancer cell lines with a higher MAT2A C/N ratio were more invasive. (4) Conclusions: the subcellular localization of MAT2A may affect its functions, and elevated MAT2A C/N ratio in breast cancer cells is associated with increased invasiveness. MAT2A C/N expression ratio determined by IHC staining could serve as a novel independent prognostic marker for breast cancer.
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Firestone RS, Feng M, Basu I, Peregrina K, Augenlicht LH, Schramm VL. Transition state analogue of MTAP extends lifespan of APC Min/+ mice. Sci Rep 2021; 11:8844. [PMID: 33893330 PMCID: PMC8065027 DOI: 10.1038/s41598-021-87734-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 03/23/2021] [Indexed: 01/03/2023] Open
Abstract
A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP-/- cancer cell lines.
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Affiliation(s)
- Ross S Firestone
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mu Feng
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Indranil Basu
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Karina Peregrina
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Leonard H Augenlicht
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
| | - Vern L Schramm
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids. Trends Cancer 2021; 7:682-699. [PMID: 33736962 DOI: 10.1016/j.trecan.2021.02.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 11/22/2022]
Abstract
Overcoming anticancer drug resistance is a major challenge in cancer therapy, requiring innovative strategies that consider the extensive tumor heterogeneity and adaptability. We provide recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. AAs sustain the acquisition of anticancer resistance by providing essential building blocks for biosynthetic pathways and for maintaining a balanced redox status, and modulating the epigenetic profile of both malignant and non-malignant cells. In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies. These findings shed new light on the possibility of targeting nonresponding tumors by modulating AA availability through pharmacological or dietary interventions.
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Higuchi T, Han Q, Sugisawa N, Yamamoto J, Yamamoto N, Hayashi K, Kimura H, Miwa S, Igarashi K, Bouvet M, Singh SR, Tsuchiya H, Hoffman RM. Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer. Cancer Genomics Proteomics 2021; 18:113-120. [PMID: 33608308 DOI: 10.21873/cgp.20246] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/31/2020] [Accepted: 01/19/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND/AIM Cancers are selectively sensitive to methionine (MET) restriction (MR) due to their addiction to MET which is overused for elevated methylation reactions. MET addiction of cancer was discovered by us 45 years ago. MR of cancer results in depletion of S-adenosylmethionine (SAM) for transmethylation reactions, resulting in selective cancer-growth arrest in the late S/G2-phase of the cell cycle. The aim of the present study was to determine if blockade of the MET-methylation axis is a highly-effective strategy for cancer chemotherapy. MATERIALS AND METHODS In the present study, we demonstrated the efficacy of MET-methylation-axis blockade using MR by oral-recombinant methioninase (o-rMETase) combined with decitabine (DAC), an inhibitor of DNA methylation, and an inhibitor of SAM synthesis, cycloleucine (CL). We determined a proof-of-concept of the efficacy of the MET-methylation-axis blockade on a recalcitrant undifferentiated/unclassified soft-tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) mouse model. RESULTS The o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis. CONCLUSION The new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.
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Affiliation(s)
- Takashi Higuchi
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A.,Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | | | - Norihiko Sugisawa
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Jun Yamamoto
- AntiCancer, Inc., San Diego, CA, U.S.A.,Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Norio Yamamoto
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | - Katsuhiro Hayashi
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | - Hiroaki Kimura
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | - Shinji Miwa
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | - Kentaro Igarashi
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
| | - Michael Bouvet
- Department of Surgery, University of California, San Diego, CA, U.S.A
| | - Shree Ram Singh
- Basic Research Laboratory, National Cancer Institute, Frederick, MD, U.S.A.
| | - Hiroyuki Tsuchiya
- Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan;
| | - Robert M Hoffman
- AntiCancer, Inc., San Diego, CA, U.S.A.; .,Department of Surgery, University of California, San Diego, CA, U.S.A
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Vaghari-Tabari M, Ferns GA, Qujeq D, Andevari AN, Sabahi Z, Moein S. Signaling, metabolism, and cancer: An important relationship for therapeutic intervention. J Cell Physiol 2021; 236:5512-5532. [PMID: 33580511 DOI: 10.1002/jcp.30276] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 11/05/2022]
Abstract
In cancerous cells, significant changes occur in the activity of signaling pathways affecting a wide range of cellular activities ranging from growth and proliferation to apoptosis, invasiveness, and metastasis. Extensive changes also happen with respect to the metabolism of a cancerous cell encompassing a wide range of functions that include: nutrient acquisition, biosynthesis of macromolecules, and energy generation. These changes are important and some therapeutic approaches for treating cancers have focused on targeting the metabolism of cancerous cells. Oncogenes and tumor suppressor genes have a significant effect on the metabolism of cells. There appears to be a close interaction between metabolism and the signaling pathways in a cancerous cell, in which the interaction provides the metabolic needs of a cancerous cell for uncontrolled proliferation, resistance to apoptosis, and metastasis. In this review, we have reviewed the latest findings in this regard and briefly review the most recent research findings regarding targeting the metabolism of cancer cells as a therapeutic approach for treatment of cancer.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gordon A Ferns
- Department of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex, UK
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Ali Nosrati Andevari
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Zahra Sabahi
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Altundag Ö, Çelebi-Saltik B. From Embryo to Adult: One Carbon Metabolism in Stem Cells. Curr Stem Cell Res Ther 2021; 16:175-188. [PMID: 32652922 DOI: 10.2174/1574888x15666200712191308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/16/2020] [Accepted: 04/23/2020] [Indexed: 11/22/2022]
Abstract
Stem cells are undifferentiated cells with self-renewal property and varying differentiation potential that allow the regeneration of tissue cells of an organism throughout adult life beginning from embryonic development. Through the asymmetric cell divisions, each stem cell replicates itself and produces an offspring identical with the mother cell, and a daughter cell that possesses the characteristics of a progenitor cell and commits to a specific lineage to differentiate into tissue cells to maintain homeostasis. To maintain a pool of stem cells to ensure tissue regeneration and homeostasis, it is important to regulate the metabolic functioning of stem cells, progenitor cells and adult tissue stem cells that will meet their internal and external needs. Upon fertilization, the zygote transforms metabolic reprogramming while implantation, embryonic development, organogenesis processes and after birth through adult life. Metabolism in stem cells is a concept that is relatively new to be enlightened. There are no adequate and comprehensive in vitro studies on the comparative analysis of the effects of one-carbon (1-C) metabolism on fetal and adult stem cells compared to embryonic and cancer stem cells' studies that have been reported recently. Since 1-C metabolism is linking parental environmental/ dietary factors and fetal development, investigating the epigenetic, genetic, metabolic and developmental effects on adult period is necessary. Several mutations and abnormalities in 1-C metabolism have been noted in disease changing from diabetes, cancer, pregnancy-related outcomes such as pre-eclampsia, spontaneous abortion, placental abruption, premature delivery, and cardiovascular diseases. In this review, the effects of 1-C metabolism, mainly the methionine and folate metabolism, in stem cells that exist in different developmental stages will be discussed.
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Affiliation(s)
- Özlem Altundag
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, 06100, Sihhiye, Ankara, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, 06100, Sihhiye, Ankara, Turkey
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Sugisawa N, Yamamoto J, Han Q, Tan Y, Tashiro Y, Nishino H, Inubushi S, Hamada K, Kawaguchi K, Unno M, Bouvet M, Hoffman RM. Triple-Methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model. Pancreas 2021; 50:93-98. [PMID: 33370029 DOI: 10.1097/mpa.0000000000001709] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer. METHODS The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control). RESULTS Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%). CONCLUSIONS This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Kei Kawaguchi
- Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
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Zhang B, Gu Y, Jiang G. Expression and Prognostic Characteristics of m 6 A RNA Methylation Regulators in Breast Cancer. Front Genet 2020; 11:604597. [PMID: 33362863 PMCID: PMC7758326 DOI: 10.3389/fgene.2020.604597] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose N6-methyladenosine (m6A) is the most prevalent modification in mRNA methylation which has a wide effect on biological functions. This study aims to figure out the efficacy of m6A RNA methylation regulator-based biomarkers with prognostic significance in breast cancer. Patients and Methods The 23 RNA methylation regulators were firstly analyzed through ONCOMINE, then relative RNA-seq transcriptome and clinical data of 1,096 breast cancer samples and 112 normal tissue samples were acquired from The Cancer Gene Atlas (TCGA) database. The expressive distinction was also showed by the Gene Expression Omnibus (GEO) database. The gene expression data of m6A RNA regulators in human tissues were acquired from the Genotype-Tissue Expression (GTEx) database. The R v3.5.1 and other online tools such as STRING, bc-GeneExminer v4.5, Kaplan-Meier Plotter were applied for bioinformatics analysis. Results Results from ONCOMINE, TCGA, and GEO databases showed distinctive expression and clinical correlations of m6A RNA methylation regulators in breast cancer patients. The high expression of YTHDF3, ZC3H13, LRPPRC, and METTL16 indicated poor survival rate in patients with breast cancer, while high expression of RBM15B pointed to a better survival rate. Both univariate and multivariate Cox regression analyses revealed that age and risk scores were related to overall survival (OS). Univariate analysis also delineated that stage, tumor (T) status, lymph node (N) status, and metastasis (M) status were associated with OS. From another perspective, Kaplan-Meier Plotter platform showed that the relatively high expression of YTHDF3 and LRPPRC and the relatively low expression of RBM15B, ZC3H13, and METTL16 in breast cancer patients had worse Relapse-Free Survival (RFS). Breast Cancer Gene-Expression Miner v4.5 showed that LRPPRC level was negatively associated with ER and PR expression, while METTL16, RBM15B, ZC3H13 level was positively linked with ER and PR expression. In HER-2 (+) breast cancer patients, the expression of LRPPRC, METTL16, RBM15B, and ZC3H13 were all lower than the HER-2 (−) group. Conclusion The significant difference in expression levels and prognostic value of m6A RNA methylation regulators were analyzed and validated in this study. This signature revealed the potential therapeutic value of m6A RNA methylation regulators in breast cancer.
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Affiliation(s)
- Bo Zhang
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanlin Gu
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guoqin Jiang
- General Surgery Department, The Second Affiliated Hospital of Soochow University, Suzhou, China
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