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Yang SF, Chen XC, Pan YJ. Microbiota-derived metabolites in tumorigenesis: mechanistic insights and therapeutic implications. Front Pharmacol 2025; 16:1598009. [PMID: 40444051 PMCID: PMC12119621 DOI: 10.3389/fphar.2025.1598009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
Intestinal microbiota is a complex ecosystem of microorganisms that perform diverse metabolic activities to maintain gastrointestinal homeostasis. These microorganisms provide energy and nutrients for growth and reproduction while producing numerous metabolites including lipopolysaccharides (LPS), Bacteroides fragilis toxin (BFT), bile acids (BAs), polyamines (PAs), and short-chain fatty acids (SCFAs). These metabolites are linked to inflammation and various metabolic diseases, such as obesity, type-2 diabetes, non-alcoholic fatty liver disease, cardiometabolic disease, and malnutrition. In addition, they may contribute to tumorigenesis. Evidence suggests that these microbes can increase the susceptibility to certain cancers and affect treatment responses. In this review, we discuss the current knowledge on how the gut microbiome and its metabolites influence tumorigenesis, highlighting the potential molecular mechanisms and prospects for basic and translational research in this emerging field.
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Affiliation(s)
| | | | - Yao-Jie Pan
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
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2
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Sena LA. Polyamine metabolism in prostate cancer. Curr Opin Oncol 2025; 37:223-232. [PMID: 40071465 PMCID: PMC11971019 DOI: 10.1097/cco.0000000000001134] [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: 04/05/2025]
Abstract
PURPOSE OF REVIEW Normal and malignant prostate engage in high rates of de novo polyamine synthesis. This review considers how polyamine metabolism regulates prostate cancer initiation and progression. RECENT FINDINGS The androgen receptor (AR) establishes a metabolic program to drive robust polyamine synthesis in the normal prostate. Upon malignant transformation, this AR-driven metabolic program persists and is optimized for oncogenesis by the proto-oncogene MYC and/or alterations to PI3K signaling. A deeper understanding of the function of polyamines in prostate cancer may be obtained by considering their function in the normal prostate. SUMMARY Recent findings support ongoing research into the role of polyamines in driving prostate cancer initiation and progression and suggest targeting polyamine metabolism remains a promising therapeutic strategy for prevention and treatment of prostate cancer.
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Affiliation(s)
- Laura A Sena
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University; Baltimore, Maryland, USA
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3
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Nakanishi S, Cleveland JL. Genetic analyses of Myc and hypusine circuits in tumorigenesis. Methods Enzymol 2025; 715:1-17. [PMID: 40382132 DOI: 10.1016/bs.mie.2025.02.005] [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: 05/20/2025]
Abstract
A prominent metabolic pathway induced by MYC family oncoproteins in cancer is the polyamine-hypusine circuit, which post-translationally modifies a specific lysine residue of eukaryotic translation initiation factor 5 A (eIF5A) with a unique amino acid coined hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. This modification occurs in a two-step process, whereby the aminobutyl group of the polyamine spermidine is covalently linked to lysine-50 of eIF5A via deoxyhypusine synthase (DHPS) to form the intermediate deoxyhypusinated eIF5A, which is subsequently hydoxylated by deoxyhypusine hydroxylase (DOHH) to form the fully mature eIF5AHyp. As a result, eIF5AHyp is elevated in MYC-driven cancers. Recently it has become evident that eIF5AHyp (i) plays key roles in the development, progression and maintenance of tumors; and (ii) eIF5AHyp functions are often tissue/cell context-specific. Thus, it is important to mechanistically assess how eIF5AHyp affects normal cells and tumorigenesis using suitable in vivo and ex vivo models. In this chapter, we describe the methods used in our laboratory to assess the effects of MYC-polyamine-hypusine axis on the development and maintenance of MYC-driven B-cell lymphoma. The goals of this chapter are twofold. First, we discuss genetic and cell biological approaches that can be applied to assess roles of eIF5AHyp on lymphoma and normal B cell development. Second, we discuss methods that can be used to assess the roles of eIF5AHyp on the growth and maintenance of lymphoma. Collectively, these approaches provide a template that can be applied to evaluate roles of any putative regulator of the development and/or maintenance of lymphoma.
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Affiliation(s)
- Shima Nakanishi
- Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - John L Cleveland
- Department of Tumor Microenvironment & Metastasis, Moffitt Cancer Center & Research Institute, Tampa, FL, United States.
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Swanson MA, Szarowicz C, Pike ST, Schultz CR, Bachmann AS, Dowling TC. Novel LC-MS/MS assay to quantify D,L-alpha-difluoromethylornithine (DFMO) in mouse plasma. Methods Enzymol 2025; 715:423-436. [PMID: 40382153 DOI: 10.1016/bs.mie.2025.01.036] [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: 05/20/2025]
Abstract
D,L-alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC) that is being investigated to treat cancers such as pediatric neuroblastoma. A novel and sensitive LC-MS/MS assay was developed and validated to quantify DFMO concentrations in support of pre-clinical pharmacokinetic studies in mice. The study was performed using a Shimadzu triple quad LC-MS/MS equipped with an Atlantis HILIC Silica 3 µm 2.1 × 100 mm column, and an isocratic mobile phase (75:25 acetonitrile and 0.2 % formic acid) at a flow rate of 0.5 mL/min. Multiple Reaction Monitoring (MRM) was used to identify the precursor ion (183 m/z) with quantification of daughter ions at transitions of 183 > 120.10, 183 > 166.10, and 183 > 80.05. Plasma standards and quality control samples (20 µL) were processed using protein precipitation with cold acetonitrile. The lower limit of detection (LLOQ) was 5 ng/mL. Assay performance was determined from multiple runs (n = 10) with standards ranging from 250-50,000 ng/mL and three levels of quality control (500, 4000, and 40,000 ng/mL). Standard curves were linear with r2 values between 0.9960 and 0.9999. Quality control samples were stable and exhibited maximum inter-day % bias of ≤3 % and CV% of ≤0.7 %. The assay was successfully applied to an in vivo study to determine the pharmacokinetics of DFMO in athymic nu/nu mice.
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Affiliation(s)
- Matthew A Swanson
- Department of Biological Sciences, College of Arts and Sciences, Ferris State University, Big Rapids, MI, United States
| | - Carlye Szarowicz
- Department of Biological Sciences, College of Arts and Sciences, Ferris State University, Big Rapids, MI, United States
| | - Schuyler T Pike
- Department of Biological Sciences, College of Arts and Sciences, Ferris State University, Big Rapids, MI, United States
| | - Chad R Schultz
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - André S Bachmann
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
| | - Thomas C Dowling
- Department of Pharmaceutical Sciences, College of Pharmacy, Ferris State University, Big Rapids, MI, United States.
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5
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Sesen J, Martinez T, Busatto S, Poluben L, Nassour H, Stone C, Ashok K, Moses MA, Smith ER, Ghalali A. AZIN1 level is increased in medulloblastoma and correlates with c-Myc activity and tumor phenotype. J Exp Clin Cancer Res 2025; 44:56. [PMID: 39962590 PMCID: PMC11831846 DOI: 10.1186/s13046-025-03274-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/02/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND AZIN1 is a cell cycle regulator that is upregulated in a variety of cancers. AZIN1 overexpression can induce a more aggressive tumor phenotype via increased binding and resultant inhibition of antizyme. Antizyme is a protein that normally functions as an anti-tumor regulator that facilitates the deactivation of several growth-promoting proteins including c-Myc. MYC plays a critical role in medulloblastoma pathogenesis. Its amplification serves as a defining characteristic of group 3 medulloblastomas, associated with the most aggressive clinical course, greater frequency of metastases, and shorter survival times. METHODS Medulloblastoma tissues (68 TMA, and 45 fresh tissues, and 31 controls) were stained (fluorescence and immunohistochemical) for AZIN1. Western blotting and ELISA were used to detect the AZIN1 level. Phenotypically aggressive cellular features were measured by increased invasion, colony formation and proliferation. CRISPR-Cas9-mediated AZIN1 knocked-out cells were orthotopically implanted in the cerebellum of nude mice (n = 8/group) with a stereotactic frame. Tumor growth was monitored using the In Vivo Imaging System (IVIS). RESULTS Here, we investigated the role of AZIN1 expression in medulloblastoma. We found that overexpression of AZIN1 in medulloblastoma cells induces phenotypically aggressive features. Conducting in vivo studies we found that knocking-out AZIN1 in tumors corresponds with reduced tumor progression and prolonged survival. Clinical specimens are revealing that AZIN1 is highly expressed and directly correlates with MYC amplification status in patients. CONCLUSION These data implicate AZIN1 as a putative regulator of medulloblastoma pathogenesis and suggest that it may have clinical application as both a biomarker and novel therapeutic target.
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Affiliation(s)
- Julie Sesen
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tyra Martinez
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
| | - Sara Busatto
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Larysa Poluben
- Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Hassan Nassour
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Caroline Stone
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
| | - Karthik Ashok
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
| | - Marsha A Moses
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Edward R Smith
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Aram Ghalali
- Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.
- Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
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Ji G, Liu J, Zhao Z, Lan J, Yang Y, Wang Z, Feng H, Ji K, Jiang X, Xia H, Wei G, Zhang Y, Zhang Y, Du X, Wang Y, Yang Y, Liu Z, Zhang K, Mei Q, Sun R, Lu H. Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404853. [PMID: 39058337 PMCID: PMC11516096 DOI: 10.1002/advs.202404853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/27/2024] [Indexed: 07/28/2024]
Abstract
Breast cancer patients may initially benefit from cytotoxic chemotherapy but experience treatment resistance and relapse. Chemoresistant breast cancer stem cells (BCSCs) play a pivotal role in cancer recurrence and metastasis, however, identification and eradication of BCSC population in patients are challenging. Here, an mRNA-based BCSC signature is developed using machine learning strategy to evaluate cancer stemness in primary breast cancer patient samples. Using the BCSC signature, a critical role of polyamine anabolism in the regulation of chemotherapy-induced BCSC enrichment, is elucidated. Mechanistically, two key polyamine anabolic enzymes, ODC1 and SRM, are directly activated by transcription factor HIF-1 in response to chemotherapy. Genetic inhibition of HIF-1-controlled polyamine anabolism blocks chemotherapy-induced BCSC enrichment in vitro and in xenograft mice. A novel specific HIF-1 inhibitor britannin is identified through a natural compound library screening, and demonstrate that coadministration of britannin efficiently inhibits chemotherapy-induced HIF-1 transcriptional activity, ODC1 and SRM expression, polyamine levels, and BCSC enrichment in vitro and in xenograft and autochthonous mouse models. The findings demonstrate the key role of polyamine anabolism in BCSC regulation and provide a new strategy for breast cancer treatment.
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Affiliation(s)
- Guangyu Ji
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
- School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan250012China
| | - Jia Liu
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Zhiqun Zhao
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Jie Lan
- Department of Radiation OncologyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China
| | - You Yang
- Department of Pediatrics (Children Hematological Oncology)Birth Defects and Childhood Hematological Oncology LaboratoryThe Affiliated Hospital of Southwest Medical UniversitySichuan Clinical Research Center for Birth DefectsLuzhou646000China
| | - Zheng Wang
- Department of UrologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan250021China
| | - Huijing Feng
- Cancer Center, Shanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
| | - Kai Ji
- Shandong Helix Matrix Data TechnologyJinan250014China
| | - Xiaofeng Jiang
- Youth League CommitteeQilu HospitalShandong UniversityJinan250012China
| | - Huize Xia
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Guangyao Wei
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Yajing Zhang
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Yuhong Zhang
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Xinlong Du
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Yawen Wang
- Department of Breast Surgery, General SurgeryQilu HospitalShandong UniversityJinan250012China
| | - Yuanyuan Yang
- Shandong Artificial Intelligence InstituteQilu University of Technology (Shandong Academy of Sciences)Jinan250399China
| | - Zhaojian Liu
- School of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan250012China
| | - Kai Zhang
- Department of Breast Surgery, General SurgeryQilu HospitalShandong UniversityJinan250012China
| | - Qi Mei
- Cancer Center, Shanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Department of Oncology, Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Rong Sun
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
| | - Haiquan Lu
- The Second Hospital and Advanced Medical Research InstituteCheeloo College of MedicineShandong UniversityJinan250012China
- Key Laboratory for Experimental Teratology of the Ministry of EducationCheeloo College of MedicineShandong UniversityJinan250012China
- Center for Reproductive MedicineShandong UniversityJinan250001China
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7
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Emmons-Bell M, Forsyth G, Sundquist A, Oldeman S, Gardikioti A, de Souza R, Coene J, Kamel MH, Ayyapan S, Fuchs HA, Verhelst S, Smeeton J, Musselman CA, Schvartzman JM. Polyamines regulate cell fate by altering the activity of histone-modifying enzymes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.02.600738. [PMID: 39005392 PMCID: PMC11244958 DOI: 10.1101/2024.07.02.600738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation and that inhibiting polyamine synthesis leads to a differentiated-like cell state. Polyamines concentrate in the nucleus and are further enriched in the nucleoli of cells in culture and in vivo . Loss of polyamines drives changes in chromatin accessibility that correlate with altered histone post-translational modifications. Polyamines interact electrostatically with DNA on the nucleosome core, stabilizing histone tails in conformations accessible to modifying enzymes. These data reveal a mechanism by which an abundant metabolite influences chromatin structure and function in a non-sequence specific manner, facilitating chromatin remodeling during reprogramming and limiting it during fate commitment.
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8
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Sahu PN, Sen A. Preventing Cancer by Inhibiting Ornithine Decarboxylase: A Comparative Perspective on Synthetic vs. Natural Drugs. Chem Biodivers 2024; 21:e202302067. [PMID: 38404009 DOI: 10.1002/cbdv.202302067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/22/2024] [Accepted: 02/24/2024] [Indexed: 02/27/2024]
Abstract
This perspective delves into the investigation of synthetic and naturally occurring inhibitors, their patterns of inhibition, and the effectiveness of newly utilized natural compounds as inhibitors targeting the Ornithine decarboxylase enzyme. This enzyme is known to target the MYC oncogene, thereby establishing a connection between polyamine metabolism and oncogenesis in both normal and cancerous cells. ODC activation and heightened polyamine activity are associated with tumor development in numerous cancers and fluctuations in ODC protein levels exert a profound influence on cellular activity for inhibition or suppressing tumor cells. This perspective outlines efforts to develop novel drugs, evaluate natural compounds, and identify promising inhibitors to address gaps in cancer prevention, highlighting the potential of newly designed synthetic moieties and natural flavonoids as alternatives. It also discusses natural compounds with potential as enhanced inhibitors.
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Affiliation(s)
- Preeti Nanda Sahu
- Department of Chemistry, (CMDD Lab) GITAM (Deemed to be), University, Rushikonda, Visakhapatnam, 530045, India
| | - Anik Sen
- Department of Chemistry, (CMDD Lab) GITAM (Deemed to be), University, Rushikonda, Visakhapatnam, 530045, India
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9
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Hogarty MD, Ziegler DS, Franson A, Chi YY, Tsao-Wei D, Liu K, Vemu R, Gerner EW, Bruckheimer E, Shamirian A, Hasenauer B, Balis FM, Groshen S, Norris MD, Haber M, Park JR, Matthay KK, Marachelian A. Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial. Br J Cancer 2024; 130:788-797. [PMID: 38200233 PMCID: PMC10912730 DOI: 10.1038/s41416-023-02525-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. METHODS Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support. RESULTS Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day. CONCLUSION High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].
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Affiliation(s)
- Michael D Hogarty
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
| | - David S Ziegler
- Children's Cancer Institute, Lowy Cancer Research Centre, Randwick, NSW, Australia
- School of Women's and Children's Health, University of New South Wales, Sydney, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Andrea Franson
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yueh-Yun Chi
- Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Denice Tsao-Wei
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kangning Liu
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Rohan Vemu
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | - Anasheh Shamirian
- Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Beth Hasenauer
- Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Frank M Balis
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Susan Groshen
- Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Murray D Norris
- Children's Cancer Institute, Lowy Cancer Research Centre, Randwick, NSW, Australia
| | - Michelle Haber
- Children's Cancer Institute, Lowy Cancer Research Centre, Randwick, NSW, Australia
| | - Julie R Park
- St. Jude Children's Research Hospital, University of Tennessee, Memphis, TN, USA
| | - Katherine K Matthay
- UCSF Benioff Children's Hospital, UCSF School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Araz Marachelian
- Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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10
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Wolpaw AJ, Dang CV. Pathways Involved in the Effect of Eflornithine in Neuroblastoma. J Clin Oncol 2024; 42:116-119. [PMID: 37883720 DOI: 10.1200/jco.23.01783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 10/28/2023] Open
Affiliation(s)
- Adam J Wolpaw
- Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Chi V Dang
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD
- Ludwig Institute for Cancer Research, New York, NY
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11
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Brooks WH. Polyamine Dysregulation and Nucleolar Disruption in Alzheimer's Disease. J Alzheimers Dis 2024; 98:837-857. [PMID: 38489184 PMCID: PMC11091575 DOI: 10.3233/jad-231184] [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] [Accepted: 02/09/2024] [Indexed: 03/17/2024]
Abstract
A hypothesis of Alzheimer's disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer's disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka "nucleolar satellite") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer's, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases.
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12
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Elmarsafawi AG, Hesterberg RS, Fernandez MR, Yang C, Darville LN, Liu M, Koomen JM, Phanstiel O, Atkins R, Mullinax JE, Pilon-Thomas SA, Locke FL, Epling-Burnette PK, Cleveland JL. Modulating the polyamine/hypusine axis controls generation of CD8+ tissue-resident memory T cells. JCI Insight 2023; 8:e169308. [PMID: 37581943 PMCID: PMC10561731 DOI: 10.1172/jci.insight.169308] [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: 03/22/2023] [Accepted: 08/08/2023] [Indexed: 08/17/2023] Open
Abstract
Glutaminolysis is a hallmark of the activation and metabolic reprogramming of T cells. Isotopic tracer analyses of antigen-activated effector CD8+ T cells revealed that glutamine is the principal carbon source for the biosynthesis of polyamines putrescine, spermidine, and spermine. These metabolites play critical roles in activation-induced T cell proliferation, as well as for the production of hypusine, which is derived from spermidine and is covalently linked to the translation elongation factor eukaryotic translation initiation factor 5A (eIF5A). Here, we demonstrated that the glutamine/polyamine/hypusine axis controlled the expression of CD69, an important regulator of tissue-resident memory T cells (Trm). Inhibition of this circuit augmented the development of Trm cells ex vivo and in vivo in the BM, a well-established niche for Trm cells. Furthermore, blocking the polyamine/hypusine axis augmented CD69 expression as well as IFN-γ and TNF-α production in (a) human CD8+ T cells from peripheral blood and sarcoma tumor infiltrating lymphocytes and (b) human CD8+ CAR-T cells. Collectively, these findings support the notion that the polyamine-hypusine circuit can be exploited to modulate Trm cells for therapeutic benefit.
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Affiliation(s)
- Aya G. Elmarsafawi
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
- Department of Tumor Biology and
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Rebecca S. Hesterberg
- Department of Tumor Biology and
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
- Cancer Biology PhD Program, University of South Florida, Tampa, Florida, USA
| | | | | | - Lancia N.F. Darville
- Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Min Liu
- Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - John M. Koomen
- Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Otto Phanstiel
- Department of Medical Education, University of Central Florida College of Medicine, Orlando, Florida, USA
| | | | | | - Shari A. Pilon-Thomas
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Frederick L. Locke
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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13
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Nakanishi S, Li J, Berglund AE, Kim Y, Zhang Y, Zhang L, Yang C, Song J, Mirmira RG, Cleveland JL. The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma. Blood Cancer Discov 2023; 4:294-317. [PMID: 37070973 PMCID: PMC10320645 DOI: 10.1158/2643-3230.bcd-22-0162] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/01/2023] [Accepted: 04/13/2023] [Indexed: 04/19/2023] Open
Abstract
The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given this, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which posttranslationally modifies the eukaryotic translation factor eIF5A. The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where the loss of eIF5A hypusination abolishes malignant transformation of MYC-overexpressing B cells. Mechanistically, integrating RNA sequencing, ribosome sequencing, and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-S phase cell-cycle progression and DNA replication. This circuit thus controls MYC's proliferative response, and it is also activated across multiple malignancies. These findings suggest the hypusine circuit as a therapeutic target for several human tumor types. SIGNIFICANCE Elevated EIF5A and the polyamine-hypusine circuit are manifest in many malignancies, including MYC-driven tumors, and eIF5A hypusination is necessary for MYC proliferative signaling. Not-ably, this circuit controls an oncogenic translational program essential for the development and maintenance of MYC-driven lymphoma, supporting this axis as a target for cancer prevention and treatment. See related commentary by Wilson and Klein, p. 248. This article is highlighted in the In This Issue feature, p. 247.
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Affiliation(s)
- Shima Nakanishi
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Jiannong Li
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Anders E. Berglund
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Youngchul Kim
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Yonghong Zhang
- Department of Bioinformatics and Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Ling Zhang
- Department of Pathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Chunying Yang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Jinming Song
- Department of Pathology and Laboratory Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | | | - John L. Cleveland
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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14
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Coni S, Bordone R, Ivy DM, Yurtsever ZN, Di Magno L, D'Amico R, Cesaro B, Fatica A, Belardinilli F, Bufalieri F, Maroder M, De Smaele E, Di Marcotullio L, Giannini G, Agostinelli E, Canettieri G. Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation. Cancer Lett 2023; 559:216120. [PMID: 36893894 DOI: 10.1016/j.canlet.2023.216120] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/09/2023]
Abstract
A key mechanism driving colorectal cancer (CRC) development is the upregulation of MYC and its targets, including ornithine decarboxylase (ODC), a master regulator of polyamine metabolism. Elevated polyamines promote tumorigenesis in part by activating DHPS-mediated hypusination of the translation factor eIF5A, thereby inducing MYC biosynthesis. Thus, MYC, ODC and eIF5A orchestrate a positive feedback loop that represents an attractive therapeutic target for CRC therapy. Here we show that combined inhibition of ODC and eIF5A induces a synergistic antitumor response in CRC cells, leading to MYC suppression. We found that genes of the polyamine biosynthesis and hypusination pathways are significantly upregulated in colorectal cancer patients and that inhibition of ODC or DHPS alone limits CRC cell proliferation through a cytostatic mechanism, while combined ODC and DHPS/eIF5A blockade induces a synergistic inhibition, accompanied to apoptotic cell death in vitro and in mouse models of CRC and FAP. Mechanistically, we found that this dual treatment causes complete inhibition of MYC biosynthesis in a bimodal fashion, by preventing translational elongation and initiation. Together, these data illustrate a novel strategy for CRC treatment, based on the combined suppression of ODC and eIF5A, which holds promise for the treatment of CRC.
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Affiliation(s)
- Sonia Coni
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy.
| | - Rosa Bordone
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Devon Michael Ivy
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Zuleyha Nihan Yurtsever
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Laura Di Magno
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Rodrigo D'Amico
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Bianca Cesaro
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Alessandro Fatica
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Francesca Belardinilli
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Francesca Bufalieri
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Marella Maroder
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University, 00161, Rome, Italy
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy
| | - Enzo Agostinelli
- International Polyamines Foundation-ONLUS, Via del Forte Tiburtino 98, 00159, Rome, Italy; Department of Sense Organs, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 151, 00155, Rome, Italy
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161, Rome, Italy; IRCCS Neuromed S.p.A., Via Atinense 18, Pozzilli, Isernia, Italy.
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15
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Lee MS, Dennis C, Naqvi I, Dailey L, Lorzadeh A, Ye G, Zaytouni T, Adler A, Hitchcock DS, Lin L, Hoffman MT, Bhuiyan AM, Barth JL, Machacek ME, Mino-Kenudson M, Dougan SK, Jadhav U, Clish CB, Kalaany NY. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer. Nature 2023; 616:339-347. [PMID: 36991126 PMCID: PMC10929664 DOI: 10.1038/s41586-023-05891-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/24/2023] [Indexed: 03/30/2023]
Abstract
There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.
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Affiliation(s)
- Min-Sik Lee
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Courtney Dennis
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Insia Naqvi
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Lucas Dailey
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Alireza Lorzadeh
- Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - George Ye
- Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Tamara Zaytouni
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Ashley Adler
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Daniel S Hitchcock
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Lin Lin
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA
| | - Megan T Hoffman
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Aladdin M Bhuiyan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Immunology, Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jaimie L Barth
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Miranda E Machacek
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Unmesh Jadhav
- Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Clary B Clish
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nada Y Kalaany
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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16
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Chen Y, León-Letelier RA, Abdel Sater AH, Vykoukal J, Dennison JB, Hanash S, Fahrmann JF. c-MYC-Driven Polyamine Metabolism in Ovarian Cancer: From Pathogenesis to Early Detection and Therapy. Cancers (Basel) 2023; 15:623. [PMID: 36765581 PMCID: PMC9913358 DOI: 10.3390/cancers15030623] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 01/14/2023] [Indexed: 01/20/2023] Open
Abstract
c-MYC and its paralogues MYCN and MYCL are among the most frequently amplified and/or overexpressed oncoproteins in ovarian cancer. c-MYC plays a key role in promoting ovarian cancer initiation and progression. The polyamine pathway is a bona fide target of c-MYC signaling, and polyamine metabolism is strongly intertwined with ovarian malignancy. Targeting of the polyamine pathway via small molecule inhibitors has garnered considerable attention as a therapeutic strategy for ovarian cancer. Herein, we discuss the involvement of c-MYC signaling and that of its paralogues in promoting ovarian cancer tumorigenesis. We highlight the potential of targeting c-MYC-driven polyamine metabolism for the treatment of ovarian cancers and the utility of polyamine signatures in biofluids for early detection applications.
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Affiliation(s)
| | | | | | | | | | | | - Johannes F. Fahrmann
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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17
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Winkler R, Piskor EM, Kosan C. Lessons from Using Genetically Engineered Mouse Models of MYC-Induced Lymphoma. Cells 2022; 12:37. [PMID: 36611833 PMCID: PMC9818924 DOI: 10.3390/cells12010037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/06/2022] [Accepted: 12/15/2022] [Indexed: 12/25/2022] Open
Abstract
Oncogenic overexpression of MYC leads to the fatal deregulation of signaling pathways, cellular metabolism, and cell growth. MYC rearrangements are found frequently among non-Hodgkin B-cell lymphomas enforcing MYC overexpression. Genetically engineered mouse models (GEMMs) were developed to understand MYC-induced B-cell lymphomagenesis. Here, we highlight the advantages of using Eµ-Myc transgenic mice. We thoroughly compiled the available literature to discuss common challenges when using such mouse models. Furthermore, we give an overview of pathways affected by MYC based on knowledge gained from the use of GEMMs. We identified top regulators of MYC-induced lymphomagenesis, including some candidates that are not pharmacologically targeted yet.
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Affiliation(s)
| | | | - Christian Kosan
- Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, 07745 Jena, Germany
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18
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Tanaskovic N, Dalsass M, Filipuzzi M, Ceccotti G, Verrecchia A, Nicoli P, Doni M, Olivero D, Pasini D, Koseki H, Sabò A, Bisso A, Amati B. Polycomb group ring finger protein 6 suppresses Myc-induced lymphomagenesis. Life Sci Alliance 2022; 5:5/8/e202101344. [PMID: 35422437 PMCID: PMC9012912 DOI: 10.26508/lsa.202101344] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/04/2022] [Accepted: 04/04/2022] [Indexed: 12/15/2022] Open
Abstract
Max dimerizes with Mga to form the repressive complex PRC1.6; another PRC1.6 subunit, Pcgf6, suppresses Myc-induced lymphomagenesis but, unexpectedly, does so in a Mga- and PRC1.6-independent manner. Max is an obligate dimerization partner for the Myc transcription factors and for several repressors, such as Mnt, Mxd1-4, and Mga, collectively thought to antagonize Myc function in transcription and oncogenesis. Mga, in particular, is part of the variant Polycomb group repressive complex PRC1.6. Here, we show that ablation of the distinct PRC1.6 subunit Pcgf6–but not Mga–accelerates Myc-induced lymphomagenesis in Eµ-myc transgenic mice. Unexpectedly, however, Pcgf6 loss shows no significant impact on transcriptional profiles, in neither pre-tumoral B-cells, nor lymphomas. Altogether, these data unravel an unforeseen, Mga- and PRC1.6-independent tumor suppressor activity of Pcgf6.
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Affiliation(s)
| | - Mattia Dalsass
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | | | | | | | - Paola Nicoli
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Mirko Doni
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Daniela Olivero
- Laboratorio Analisi Veterinarie BiEsseA, A Company of Scil Animal Care Company Srl, Milan, Italy
| | - Diego Pasini
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Haruhiko Koseki
- Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Cellular and Molecular Medicine, Advanced Research Departments, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Arianna Sabò
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Andrea Bisso
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
| | - Bruno Amati
- European Institute of Oncology (IEO) - IRCCS, Milan, Italy
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19
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Coradduzza D, Solinas T, Azara E, Culeddu N, Cruciani S, Zinellu A, Medici S, Maioli M, Madonia M, Carru C. Plasma Polyamine Biomarker Panels: Agmatine in Support of Prostate Cancer Diagnosis. Biomolecules 2022; 12:biom12040514. [PMID: 35454104 PMCID: PMC9024899 DOI: 10.3390/biom12040514] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/10/2022] [Accepted: 03/26/2022] [Indexed: 01/03/2023] Open
Abstract
Prostate cancer is the most frequent malignant tumour among males (19%), often clinically silent and of difficult prognosis. Although several studies have highlighted the diagnostic and prognostic role of circulating biomarkers, such as PSA, their measurement does not necessarily allow the detection of the disease. Within this context, many authors suggest that the evaluation of circulating polyamines could represent a valuable tool, although several analytical problems still counteract their clinical practice. In particular, agmatine seems particularly intriguing, being a potential inhibitor of polyamines commonly derived from arginine. The aim of the present work was to evaluate the potential role of agmatine as a suitable biomarker for the identification of different classes of patients with prostate cancer (PC). For this reason, three groups of human patients—benign prostatic hyperplasia (BPH), precancerous lesion (PL), and prostate cancer (PC)—were recruited from a cohort of patients with suspected prostate cancer (n = 170), and obtained plasma was tested using the LC-HRMS method. Statistics on the receiver operating characteristics curve (ROC), and multivariate analysis were used to examine the predictive value of markers for discrimination among the three patient groups. Statistical analysis models revealed good discrimination using polyamine levels to distinguish the three classes of patients. AUC above 0.8, sensitivity ranging from 67% to 89%, specificity ranging from 74% to 89% and accuracy from 73% to 86%, considering the validation set, were achieved. Agmatine plasma levels were measured in PC (39.9 ± 12.06 ng/mL), BPH (77.62 ± 15.05 ng/mL), and PL (53.31 ± 15.27 ng/mL) patients. ROC analysis of the agmatine panel showed an AUC of 0.959 and p ≤ 0.001. These results could represent a future tool able to discriminate patients belonging to the three different clinical groups.
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Affiliation(s)
- Donatella Coradduzza
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (D.C.); (S.C.); (A.Z.); (M.M.)
| | - Tatiana Solinas
- Department of Clinical and Experimental Medicine, Urologic Clinic, University of Sassari, 07100 Sassari, Italy; (T.S.); (M.M.)
| | - Emanuela Azara
- Institute of Biomolecular Chemistry, National Research Council, 07100 Sassari, Italy; (E.A.); (N.C.)
| | - Nicola Culeddu
- Institute of Biomolecular Chemistry, National Research Council, 07100 Sassari, Italy; (E.A.); (N.C.)
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (D.C.); (S.C.); (A.Z.); (M.M.)
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (D.C.); (S.C.); (A.Z.); (M.M.)
| | - Serenella Medici
- Department of Chemistry and Pharmacy, University of Sassari, 07100 Sassari, Italy;
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (D.C.); (S.C.); (A.Z.); (M.M.)
| | - Massimo Madonia
- Department of Clinical and Experimental Medicine, Urologic Clinic, University of Sassari, 07100 Sassari, Italy; (T.S.); (M.M.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (D.C.); (S.C.); (A.Z.); (M.M.)
- Department of Biomedical Sciences and University Hospital of Sassari (AOU), 07100 Sassari, Italy
- Correspondence:
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20
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Fernandez MR, Schaub FX, Yang C, Li W, Yun S, Schaub SK, Dorsey FC, Liu M, Steeves MA, Ballabio A, Tzankov A, Chen Z, Koomen JM, Berglund AE, Cleveland JL. Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy. Cancer Res 2022; 82:1234-1250. [PMID: 35149590 DOI: 10.1158/0008-5472.can-21-1168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 12/07/2021] [Accepted: 02/08/2022] [Indexed: 11/16/2022]
Abstract
MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, amino acid transport, and amino acid and nucleotide metabolism, leading to metabolic anergy, growth arrest and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.
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Affiliation(s)
- Mario R Fernandez
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute
| | - Franz X Schaub
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute
| | - Chunying Yang
- Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute
| | - Weimin Li
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute
| | | | | | | | - Min Liu
- Proteomics Core, Moffitt Cancer Center
| | | | | | | | - Zhihua Chen
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center
| | - John M Koomen
- Department of Molecular Oncology, Moffitt Cancer Center
| | - Anders E Berglund
- Department of Biostatistics and Bioinformatics, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute
| | - John L Cleveland
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute
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21
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Asami M, Lam BYH, Ma MK, Rainbow K, Braun S, VerMilyea MD, Yeo GSH, Perry ACF. Human embryonic genome activation initiates at the one-cell stage. Cell Stem Cell 2021; 29:209-216.e4. [PMID: 34936886 PMCID: PMC8826644 DOI: 10.1016/j.stem.2021.11.012] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/24/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022]
Abstract
In human embryos, the initiation of transcription (embryonic genome activation [EGA]) occurs by the eight-cell stage, but its exact timing and profile are unclear. To address this, we profiled gene expression at depth in human metaphase II oocytes and bipronuclear (2PN) one-cell embryos. High-resolution single-cell RNA sequencing revealed previously inaccessible oocyte-to-embryo gene expression changes. This confirmed transcript depletion following fertilization (maternal RNA degradation) but also uncovered low-magnitude upregulation of hundreds of spliced transcripts. Gene expression analysis predicted embryonic processes including cell-cycle progression and chromosome maintenance as well as transcriptional activators that included cancer-associated gene regulators. Transcription was disrupted in abnormal monopronuclear (1PN) and tripronuclear (3PN) one-cell embryos. These findings indicate that human embryonic transcription initiates at the one-cell stage, sooner than previously thought. The pattern of gene upregulation promises to illuminate processes involved at the onset of human development, with implications for epigenetic inheritance, stem-cell-derived embryos, and cancer.
Gene expression initiates at the one-cell stage in human embryos Expression is of low magnitude but remains elevated until the eight-cell stage Upregulated transcripts are spliced and correspond to embryonic processes Upregulation is disrupted in morphologically abnormal one-cell embryos
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Affiliation(s)
- Maki Asami
- Laboratory of Mammalian Molecular Embryology, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, England
| | - Brian Y H Lam
- MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England
| | - Marcella K Ma
- MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England
| | - Kara Rainbow
- MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England
| | - Stefanie Braun
- Ovation Fertility Austin, Embryology and Andrology Laboratories, Austin, TX 78731, USA
| | - Matthew D VerMilyea
- Ovation Fertility Austin, Embryology and Andrology Laboratories, Austin, TX 78731, USA.
| | - Giles S H Yeo
- MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England.
| | - Anthony C F Perry
- Laboratory of Mammalian Molecular Embryology, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, England.
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22
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Harrington CT, Sotillo E, Dang CV, Thomas-Tikhonenko A. Tilting MYC toward cancer cell death. Trends Cancer 2021; 7:982-994. [PMID: 34481764 PMCID: PMC8541926 DOI: 10.1016/j.trecan.2021.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022]
Abstract
MYC oncoprotein promotes cell proliferation and serves as the key driver in many human cancers; therefore, considerable effort has been expended to develop reliable pharmacological methods to suppress its expression or function. Despite impressive progress, MYC-targeting drugs have not reached the clinic. Recent advances suggest that within a limited expression range unique to each tumor, MYC oncoprotein can have a paradoxical, proapoptotic function. Here we introduce a counterintuitive idea that modestly and transiently elevating MYC levels could aid chemotherapy-induced apoptosis and thus benefit the patients as much, if not more than MYC inhibition.
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Affiliation(s)
- Colleen T Harrington
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Elena Sotillo
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Chi V Dang
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA; Ludwig Institute for Cancer Research, New York, NY 10017, USA
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
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23
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Novita Sari I, Setiawan T, Seock Kim K, Toni Wijaya Y, Won Cho K, Young Kwon H. Metabolism and function of polyamines in cancer progression. Cancer Lett 2021; 519:91-104. [PMID: 34186159 DOI: 10.1016/j.canlet.2021.06.020] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/11/2021] [Accepted: 06/22/2021] [Indexed: 01/18/2023]
Abstract
Polyamines are essential for the proliferation, differentiation, and development of eukaryotes. They include spermine, spermidine, and the diamine precursor putrescine, and are low-molecular-weight, organic polycations with more than two amino groups. Their intracellular concentrations are strictly maintained within a specific physiological range through several regulatory mechanisms in normal cells. In contrast, polyamine metabolism is dysregulated in many neoplastic states, including cancer. In various types of cancer, polyamine levels are elevated, and crosstalk occurs between polyamine metabolism and oncogenic pathways, such as mTOR and RAS pathways. Thus, polyamines might have potential as therapeutic targets in the prevention and treatment of cancer. The molecular mechanisms linking polyamine metabolism to carcinogenesis must be unraveled to develop novel inhibitors of polyamine metabolism. This overview describes the nature of polyamines, their association with carcinogenesis, the development of polyamine inhibitors and their potential, and the findings of clinical trials.
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Affiliation(s)
- Ita Novita Sari
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea
| | - Tania Setiawan
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea
| | - Kwang Seock Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, 31151, Republic of Korea
| | - Yoseph Toni Wijaya
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea
| | - Kae Won Cho
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea; Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, 31151, Republic of Korea.
| | - Hyog Young Kwon
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-si, 31151, Republic of Korea; Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si, 31151, Republic of Korea.
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24
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Schultz CR, Swanson MA, Dowling TC, Bachmann AS. Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma. Cancer Chemother Pharmacol 2021; 88:607-617. [PMID: 34129075 DOI: 10.1007/s00280-021-04309-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/30/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Neuroblastoma (NB) is the most common extracranial solid tumor in children. Interference with the polyamine biosynthesis pathway by inhibition of MYCN-activated ornithine decarboxylase (ODC) is a validated approach. The ODC inhibitor α-difluoromethylornithine (DFMO, or Eflornithine) has been FDA-approved for the treatment of trypanosomiasis and hirsutism and has advanced to clinical cancer trials including NB as well as cancer-unrelated human diseases. One key challenge of DFMO is its rapid renal clearance and the need for high and frequent drug dosing during treatment. METHODS We performed in vivo pharmacokinetic (PK), antitumorigenic, and molecular studies with DFMO/probenecid using NB patient-derived xenografts (PDX) in mice. We used LC-MS/MS, HPLC, and immunoblotting to analyze blood, brain tissue, and PDX tumor tissue samples collected from mice. RESULTS The organic anion transport 1/3 (OAT 1/3) inhibitor probenecid reduces the renal clearance of DFMO and significantly increases the antitumor activity of DFMO in PDX of NB (P < 0.02). Excised tumors revealed that DFMO/probenecid treatment decreases polyamines putrescine and spermidine, reduces MYCN protein levels and dephosphorylates retinoblastoma (Rb) protein (p-RbSer795), suggesting DFMO/probenecid-induced cell cycle arrest. CONCLUSION Addition of probenecid as an adjuvant to DFMO therapy may be suitable to decrease overall dose and improve drug efficacy in vivo.
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Affiliation(s)
- Chad R Schultz
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 400 Monroe Ave, NW, Grand Rapids, MI, 49503, USA
| | - Matthew A Swanson
- Shimadzu Core Laboratory for Academic and Research Excellence, Ferris State University, Big Rapids, MI, USA
| | - Thomas C Dowling
- Department of Pharmaceutical Sciences, College of Pharmacy, Ferris State University, Big Rapids, MI, USA
| | - André S Bachmann
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, 400 Monroe Ave, NW, Grand Rapids, MI, 49503, USA.
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25
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Sagar NA, Tarafdar S, Agarwal S, Tarafdar A, Sharma S. Polyamines: Functions, Metabolism, and Role in Human Disease Management. Med Sci (Basel) 2021; 9:44. [PMID: 34207607 PMCID: PMC8293435 DOI: 10.3390/medsci9020044] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
Putrescine, spermine, and spermidine are the important polyamines (PAs), found in all living organisms. PAs are formed by the decarboxylation of amino acids, and they facilitate cell growth and development via different cellular responses. PAs are the integrated part of the cellular and genetic metabolism and help in transcription, translation, signaling, and post-translational modifications. At the cellular level, PA concentration may influence the condition of various diseases in the body. For instance, a high PA level is detrimental to patients suffering from aging, cognitive impairment, and cancer. The levels of PAs decline with age in humans, which is associated with different health disorders. On the other hand, PAs reduce the risk of many cardiovascular diseases and increase longevity, when taken in an optimum quantity. Therefore, a controlled diet is an easy way to maintain the level of PAs in the body. Based on the nutritional intake of PAs, healthy cell functioning can be maintained. Moreover, several diseases can also be controlled to a higher extend via maintaining the metabolism of PAs. The present review discusses the types, important functions, and metabolism of PAs in humans. It also highlights the nutritional role of PAs in the prevention of various diseases.
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Affiliation(s)
- Narashans Alok Sagar
- Department of Agriculture and Environmental Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat 131028, Haryana, India
- Food Microbiology Lab, Division of Livestock Products Technology, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, Uttar Pradesh, India
| | - Swarnava Tarafdar
- Department of Radiodiagnosis and Imaging, All India Institute of Medical Science, Rishikesh 249203, Uttarakhand, India;
| | - Surbhi Agarwal
- Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India;
| | - Ayon Tarafdar
- Livestock Production and Management Section, ICAR-Indian Veterinary Research Institute, Izatnagar 243122, Uttar Pradesh, India;
| | - Sunil Sharma
- Department of Agriculture and Environmental Sciences, National Institute of Food Technology Entrepreneurship and Management, Kundli, Sonepat 131028, Haryana, India
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26
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Nakanishi S, Cleveland JL. Polyamine Homeostasis in Development and Disease. MEDICAL SCIENCES (BASEL, SWITZERLAND) 2021; 9:medsci9020028. [PMID: 34068137 PMCID: PMC8162569 DOI: 10.3390/medsci9020028] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022]
Abstract
Polycationic polyamines are present in nearly all living organisms and are essential for mammalian cell growth and survival, and for development. These positively charged molecules are involved in a variety of essential biological processes, yet their underlying mechanisms of action are not fully understood. Several studies have shown both beneficial and detrimental effects of polyamines on human health. In cancer, polyamine metabolism is frequently dysregulated, and elevated polyamines have been shown to promote tumor growth and progression, suggesting that targeting polyamines is an attractive strategy for therapeutic intervention. In contrast, polyamines have also been shown to play critical roles in lifespan, cardiac health and in the development and function of the brain. Accordingly, a detailed understanding of mechanisms that control polyamine homeostasis in human health and disease is needed to develop safe and effective strategies for polyamine-targeted therapy.
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27
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Hyvönen MT, Khomutov M, Vepsäläinen J, Khomutov AR, Keinänen TA. α-Difluoromethylornithine-Induced Cytostasis is Reversed by Exogenous Polyamines, Not by Thymidine Supplementation. Biomolecules 2021; 11:biom11050707. [PMID: 34068700 PMCID: PMC8151227 DOI: 10.3390/biom11050707] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/04/2021] [Accepted: 05/06/2021] [Indexed: 12/04/2022] Open
Abstract
Polyamine spermidine is essential for the proliferation of eukaryotic cells. Administration of polyamine biosynthesis inhibitor α-difluoromethylornithine (DFMO) induces cytostasis that occurs in two phases; the early phase which can be reversed by spermidine, spermine, and some of their analogs, and the late phase which is characterized by practically complete depletion of cellular spermidine pool. The growth of cells at the late phase can be reversed by spermidine and by very few of its analogs, including (S)-1-methylspermidine. It was reported previously (Witherspoon et al. Cancer Discovery 3(9); 1072–81, 2013) that DFMO treatment leads to depletion of cellular thymidine pools, and that exogenous thymidine supplementation partially prevents DFMO-induced cytostasis without affecting intracellular polyamine pools in HT-29, SW480, and LoVo colorectal cancer cells. Here we show that thymidine did not prevent DFMO-induced cytostasis in DU145, LNCaP, MCF7, CaCo2, BT4C, SV40MES13, HepG2, HEK293, NIH3T3, ARPE19 or HT-29 cell lines, whereas administration of functionally active mimetic of spermidine, (S)-1-methylspermidine, did. Thus, the effect of thymidine seems to be specific only for certain cell lines. We conclude that decreased polyamine levels and possibly also distorted pools of folate-dependent metabolites mediate the anti-proliferative actions of DFMO. However, polyamines are necessary and sufficient to overcome DFMO-induced cytostasis, while thymidine is generally not.
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Affiliation(s)
- Mervi T. Hyvönen
- Kuopio Campus, School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; (J.V.); (T.A.K.)
- Correspondence:
| | - Maxim Khomutov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia; (M.K.); (A.R.K.)
| | - Jouko Vepsäläinen
- Kuopio Campus, School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; (J.V.); (T.A.K.)
| | - Alex R. Khomutov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia; (M.K.); (A.R.K.)
| | - Tuomo A. Keinänen
- Kuopio Campus, School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland; (J.V.); (T.A.K.)
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28
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Khan A, Gamble LD, Upton DH, Ung C, Yu DMT, Ehteda A, Pandher R, Mayoh C, Hébert S, Jabado N, Kleinman CL, Burns MR, Norris MD, Haber M, Tsoli M, Ziegler DS. Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas. Nat Commun 2021; 12:971. [PMID: 33579942 PMCID: PMC7881014 DOI: 10.1038/s41467-021-20896-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show that polyamine synthesis is upregulated in DIPG, leading to sensitivity to DFMO. DIPG cells compensate for ODC1 inhibition by upregulation of the polyamine transporter SLC3A2. Treatment with the polyamine transporter inhibitor AMXT 1501 reduces uptake of polyamines in DIPG cells, and co-administration of AMXT 1501 and DFMO leads to potent in vitro activity, and significant extension of survival in three aggressive DIPG orthotopic animal models. Collectively, these results demonstrate the potential of dual targeting of polyamine synthesis and uptake as a therapeutic strategy for incurable DIPG.
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Affiliation(s)
- Aaminah Khan
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Laura D. Gamble
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Dannielle H. Upton
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Caitlin Ung
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Denise M. T. Yu
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Anahid Ehteda
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Ruby Pandher
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Chelsea Mayoh
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Steven Hébert
- grid.14709.3b0000 0004 1936 8649Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics, McGill University, 3999 Côte Ste-Catherine Road, Montreal, QC H4A 3J1 Canada
| | - Nada Jabado
- grid.63984.300000 0000 9064 4811Department of Pediatrics, McGill University Health Center, 1001 Decarie Boulevard, Montreal, QC H4A 3J1 Canada
| | - Claudia L. Kleinman
- grid.14709.3b0000 0004 1936 8649Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Human Genetics, McGill University, 3999 Côte Ste-Catherine Road, Montreal, QC H4A 3J1 Canada
| | - Mark R. Burns
- Aminex Therapeutics Inc., Suite #364, 6947 Coal Creek Parkway SE, Newcastle, WA 98059 USA
| | - Murray D. Norris
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.1005.40000 0004 4902 0432Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Michelle Haber
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.1005.40000 0004 4902 0432Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW 2052 Australia
| | - Maria Tsoli
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia
| | - David S. Ziegler
- grid.1005.40000 0004 4902 0432Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW 2052 Australia ,grid.414009.80000 0001 1282 788XKids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, 2031 Australia
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29
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Luinenburg DG, Dinitzen AB, Flohr Svendsen A, Cengiz R, Ausema A, Weersing E, Bystrykh L, de Haan G. Persistent expression of microRNA-125a targets is required to induce murine hematopoietic stem cell repopulating activity. Exp Hematol 2021; 94:47-59.e5. [PMID: 33333212 DOI: 10.1016/j.exphem.2020.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 01/17/2023]
Abstract
MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression posttranscriptionally by binding to the 3' untranslated regions of their target mRNAs. The evolutionarily conserved microRNA-125a (miR-125a) is highly expressed in both murine and human hematopoietic stem cells (HSCs), and previous studies have found that miR-125 strongly enhances self-renewal of HSCs and progenitors. In this study we explored whether temporary overexpression of miR-125a would be sufficient to permanently increase HSC self-renewal or, rather, whether persistent overexpression of miR-125a is required. We used three complementary in vivo approaches to reversibly enforce expression of miR-125a in murine HSCs. Additionally, we interrogated the underlying molecular mechanisms responsible for the functional changes that occur in HSCs on overexpression of miR-125a. Our data indicate that continuous expression of miR-125a is required to enhance HSC activity. Our molecular analysis confirms changes in pathways that explain the characteristics of miR-125a overexpressing HSCs. Moreover, it provides several novel putative miR-125a targets, but also highlights the complex molecular changes that collectively lead to enhanced HSC function.
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Affiliation(s)
- Daniëlle G Luinenburg
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexander Bak Dinitzen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Arthur Flohr Svendsen
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Roza Cengiz
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Albertina Ausema
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ellen Weersing
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Leonid Bystrykh
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerald de Haan
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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30
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Baicalein, 7,8-Dihydroxyflavone and Myricetin as Potent Inhibitors of Human Ornithine Decarboxylase. Nutrients 2020; 12:nu12123867. [PMID: 33348871 PMCID: PMC7765794 DOI: 10.3390/nu12123867] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 11/23/2022] Open
Abstract
Background: Human ornithine decarboxylase (ODC) is a well-known oncogene, and the discovery of ODC enzyme inhibitors is a beneficial strategy for cancer therapy and prevention. Methods: We examined the inhibitory effects of a variety of flavone and flavonol derivatives on ODC enzymatic activity, and performed in silico molecular docking of baicalein, 7,8-dihydroxyflavone and myricetin to the whole dimer of human ODC to investigate the possible binding site of these compounds on ODC. We also examined the cytotoxic effects of these compounds with cell-based studies. Results: Baicalein, 7,8-dihydroxyflavone and myricetin exhibited significant ODC suppression activity with IC50 values of 0.88 µM, 2.54 µM, and 7.3 µM, respectively, which were much lower than that of the active-site irreversible inhibitor α-DL-difluoromethylornithine (IC50, the half maximal inhibitory concentration, of approximately 100 µM). Kinetic studies and molecular docking simulations suggested that baicalein, and 7,8-dihydroxyflavone act as noncompetitive inhibitors that are hydrogen-bonded to the region near the active site pocket in the dimer interface of the enzyme. Baicalein and myricetin suppress cell growth and induce cellular apoptosis, and both of these compounds suppress the ODC-evoked anti-apoptosis of cells. Conclusions: Therefore, we suggest that the flavone or flavonol derivatives baicalein, 7,8-dihydroxyflavone, and myricetin are potent chemopreventive and chemotherapeutic agents that target ODC.
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31
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Coni S, Serrao SM, Yurtsever ZN, Di Magno L, Bordone R, Bertani C, Licursi V, Ianniello Z, Infante P, Moretti M, Petroni M, Guerrieri F, Fatica A, Macone A, De Smaele E, Di Marcotullio L, Giannini G, Maroder M, Agostinelli E, Canettieri G. Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation. Cell Death Dis 2020; 11:1045. [PMID: 33303756 PMCID: PMC7729396 DOI: 10.1038/s41419-020-03174-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/11/2022]
Abstract
Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APCMin/+ mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy.
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Affiliation(s)
- Sonia Coni
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Silvia Maria Serrao
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Zuleyha Nihan Yurtsever
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Laura Di Magno
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Rosa Bordone
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Camilla Bertani
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Valerio Licursi
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Zaira Ianniello
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Paola Infante
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy
| | - Marta Moretti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Marialaura Petroni
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Francesca Guerrieri
- Cancer Research Center of Lyon (CRCL), UMR Inserm U1052/CNRS 5286, Lyon, France
| | - Alessandro Fatica
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Alberto Macone
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Lucia Di Marcotullio
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
- Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Marella Maroder
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy
| | - Enzo Agostinelli
- International Polyamines Foundation-ONLUS, Via del Forte Tiburtino 98, 00159, Rome, Italy
- Department of Sense Organs, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161, Rome, Italy
| | - Gianluca Canettieri
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
- Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Viale Regina Elena 291, 00161, Rome, Italy.
- International Polyamines Foundation-ONLUS, Via del Forte Tiburtino 98, 00159, Rome, Italy.
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32
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Ouyang Y, Wu Q, Li J, Sun S, Sun S. S-adenosylmethionine: A metabolite critical to the regulation of autophagy. Cell Prolif 2020; 53:e12891. [PMID: 33030764 PMCID: PMC7653241 DOI: 10.1111/cpr.12891] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/21/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation. Although nutrient availability strongly impacts the process of autophagy, the specific metabolites that regulate autophagic responses have not yet been determined. Recent results indicate that S-adenosylmethionine (SAM) represents a critical inhibitor of methionine starvation-induced autophagy. SAM is primarily involved in four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5'-deoxyadenosyl 5'-radical-mediated biochemical transformations. SAM is the sole methyl group donor involved in the methylation of DNA, RNA and histones, modulating the autophagic process by mediating epigenetic effects. Moreover, the metabolites of SAM, such as homocysteine, glutathione, decarboxylated SAM and spermidine, also exert important influences on the regulation of autophagy. From our perspective, nuclear-cytosolic SAM is a conserved metabolic inhibitor that connects cellular metabolic status and the regulation of autophagy. In the future, SAM might be a new target of autophagy regulators and be widely used in the treatment of various diseases.
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Affiliation(s)
- Yang Ouyang
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Qi Wu
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Juanjuan Li
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Si Sun
- Department of Clinical LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Shengrong Sun
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
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33
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Hesterberg RS, Beatty MS, Han Y, Fernandez MR, Akuffo AA, Goodheart WE, Yang C, Chang S, Colin CM, Alontaga AY, McDaniel JM, Mailloux AW, Billington JMR, Yue L, Russell S, Gillies RJ, Yun SY, Ayaz M, Lawrence NJ, Lawrence HR, Yu XZ, Fu J, Darville LN, Koomen JM, Ren X, Messina J, Jiang K, Garrett TJ, Rajadhyaksha AM, Cleveland JL, Epling-Burnette PK. Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes. Blood 2020; 136:857-870. [PMID: 32403132 PMCID: PMC7426646 DOI: 10.1182/blood.2019003257] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 04/20/2020] [Indexed: 01/08/2023] Open
Abstract
Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.
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Affiliation(s)
- Rebecca S Hesterberg
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Matthew S Beatty
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Ying Han
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Mario R Fernandez
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Afua A Akuffo
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - William E Goodheart
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Chunying Yang
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Shiun Chang
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Christelle M Colin
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Aileen Y Alontaga
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Jessica M McDaniel
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Adam W Mailloux
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Julia M R Billington
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Lanzhu Yue
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shonagh Russell
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
- Department of Cancer Physiology
| | | | | | | | - Nicholas J Lawrence
- Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL
| | | | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
| | - Jianing Fu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
| | | | - John M Koomen
- Proteomics and Metabolomics Core
- Department of Molecular Oncology, and
| | - Xiubao Ren
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Jane Messina
- Department of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Kun Jiang
- Department of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Timothy J Garrett
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL; and
| | - Anjali M Rajadhyaksha
- Pediatric Neurology, Pediatrics, Weill Family Brain and Mind Research Institute, and
- Graduate Program in Neuroscience, Weill Cornell Medical College, Cornell University, Cornell, NY
| | - John L Cleveland
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
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34
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Dong Y, Tu R, Liu H, Qing G. Regulation of cancer cell metabolism: oncogenic MYC in the driver's seat. Signal Transduct Target Ther 2020; 5:124. [PMID: 32651356 PMCID: PMC7351732 DOI: 10.1038/s41392-020-00235-2] [Citation(s) in RCA: 229] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 12/31/2022] Open
Abstract
Cancer cells must rewire cellular metabolism to satisfy the demands of unbridled growth and proliferation. As such, most human cancers differ from normal counterpart tissues by a plethora of energetic and metabolic reprogramming. Transcription factors of the MYC family are deregulated in up to 70% of all human cancers through a variety of mechanisms. Oncogenic levels of MYC regulates almost every aspect of cellular metabolism, a recently revisited hallmark of cancer development. Meanwhile, unrestrained growth in response to oncogenic MYC expression creates dependency on MYC-driven metabolic pathways, which in principle provides novel targets for development of effective cancer therapeutics. In the current review, we summarize the significant progress made toward understanding how MYC deregulation fuels metabolic rewiring in malignant transformation.
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Affiliation(s)
- Yang Dong
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Frontier Science Center for Immunology & Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China
| | - Rongfu Tu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Frontier Science Center for Immunology & Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China
| | - Hudan Liu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Frontier Science Center for Immunology & Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China
| | - Guoliang Qing
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Frontier Science Center for Immunology & Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China.
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35
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Tan SY, Kelkar Y, Hadjipanayis A, Shipstone A, Wynn TA, Hall JP. Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4 + T Cell Effector Functions and Activation-Induced Metabolic Reprogramming. THE JOURNAL OF IMMUNOLOGY 2020; 205:957-967. [PMID: 32641388 DOI: 10.4049/jimmunol.2000137] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/15/2020] [Indexed: 01/05/2023]
Abstract
Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4+ T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.
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Affiliation(s)
- Stefanie Y Tan
- Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139
| | - Yogeshwar Kelkar
- Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139
| | | | - Arun Shipstone
- Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139
| | - Thomas A Wynn
- Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139
| | - J Perry Hall
- Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139
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36
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Fan J, Feng Z, Chen N. Spermidine as a target for cancer therapy. Pharmacol Res 2020; 159:104943. [PMID: 32461185 DOI: 10.1016/j.phrs.2020.104943] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/16/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Spermidine, as a natural component from polyamine members, is originally isolated from semen and also existed in many natural plants, and can be responsible for cell growth and development in eukaryotes. The supplementation of spermidine can extend health and lifespan across species. Although the elevated levels of polyamines and the regulation of rate-limiting enzymes for polyamine metabolism have been identified as the biomarkers in many cancers, recent epidemiological data support that an increased uptake of spermidine as a caloric restriction mimic can reduce overall mortality associated with cancers. The possible mechanisms between spermidine and cancer development may be related to the precise regulation of polyamine metabolism, anti-cancer immunosurveillance, autophagy, and apoptosis. Increased intake of polyamine seems to suppress tumorigenesis, but appears to accelerate the growth of established tumors. Based on these observations and the absolute requirement for polyamines in tumor growth, spermidine could be a rational target for chemoprevention and clinical therapeutics of cancers.
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Affiliation(s)
- Jingjing Fan
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China
| | - Ziyuan Feng
- Graduate School, Wuhan Sports University, Wuhan 430079, China
| | - Ning Chen
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Health Science, Wuhan Sports University, Wuhan 430079, China.
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37
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BCG Vaccinations Upregulate Myc, a Central Switch for Improved Glucose Metabolism in Diabetes. iScience 2020; 23:101085. [PMID: 32380424 PMCID: PMC7205768 DOI: 10.1016/j.isci.2020.101085] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 04/03/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open
Abstract
Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1α/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D). Here we reveal the underlying mechanisms behind this beneficial microbe-host interaction. We show that baseline glucose transport is deficient in T1D monocytes but is improved by BCG in vitro and in vivo. We then show, using RNAseq in monocytes and CD4 T cells, that BCG treatment over 56 weeks in humans is associated with upregulation of Myc and activation of nearly two dozen Myc-target genes underlying the four metabolic pathways. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.
T1D has insufficient aerobic glycolysis; this causes insufficient sugar utilization BCG vaccine lowers blood sugar levels in T1D by augmenting aerobic glycolysis BCG-induced shift to aerobic glycolysis is associated with Myc activation Host-microbe BCG interactions through Myc activate sugar-regulating genes in T1D
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38
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Firpo MR, Mounce BC. Diverse Functions of Polyamines in Virus Infection. Biomolecules 2020; 10:E628. [PMID: 32325677 PMCID: PMC7226272 DOI: 10.3390/biom10040628] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/10/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open
Abstract
As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy.
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Affiliation(s)
| | - Bryan C. Mounce
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA;
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39
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Baluapuri A, Wolf E, Eilers M. Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol 2020; 21:255-267. [PMID: 32071436 DOI: 10.1038/s41580-020-0215-2] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2020] [Indexed: 12/13/2022]
Abstract
Oncoproteins of the MYC family are major drivers of human tumorigenesis. Since a large body of evidence indicates that MYC proteins are transcription factors, studying their function has focused on the biology of their target genes. Detailed studies of MYC-dependent changes in RNA levels have provided contrasting models of the oncogenic activity of MYC proteins through either enhancing or repressing the expression of specific target genes, or as global amplifiers of transcription. In this Review, we first summarize the biochemistry of MYC proteins and what is known (or is unclear) about the MYC target genes. We then discuss recent progress in defining the interactomes of MYC and MYCN and how this information affects central concepts of MYC biology, focusing on mechanisms by which MYC proteins modulate transcription. MYC proteins promote transcription termination upon stalling of RNA polymerase II, and we propose that this mechanism enhances the stress resilience of basal transcription. Furthermore, MYC proteins coordinate transcription elongation with DNA replication and cell cycle progression. Finally, we argue that the mechanism by which MYC proteins regulate the transcription machinery is likely to promote tumorigenesis independently of global or relative changes in the expression of their target genes.
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Affiliation(s)
- Apoorva Baluapuri
- Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany
| | - Elmar Wolf
- Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany
| | - Martin Eilers
- Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany.
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40
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Luiken S, Fraas A, Bieg M, Sugiyanto R, Goeppert B, Singer S, Ploeger C, Warsow G, Marquardt JU, Sticht C, De La Torre C, Pusch S, Mehrabi A, Gretz N, Schlesner M, Eils R, Schirmacher P, Longerich T, Roessler S. NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 2020; 39:3128-3144. [PMID: 32055024 PMCID: PMC7142020 DOI: 10.1038/s41388-020-1198-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 12/12/2019] [Accepted: 01/28/2020] [Indexed: 12/13/2022]
Abstract
NOTCH receptor signaling plays a pivotal role in liver homeostasis and hepatocarcinogenesis. However, the role of NOTCH pathway mutations and the NOTCH target gene HES5 in liver tumorigenesis are poorly understood. Here we performed whole-exome sequencing of 54 human HCC specimens and compared the prevalence of NOTCH pathway component mutations with the TCGA-LIHC cohort (N = 364). In addition, we functionally characterized the NOTCH target HES5 and the patient-derived HES5-R31G mutation in vitro and in an orthotopic mouse model applying different oncogenic backgrounds, to dissect the role of HES5 in different tumor subgroups in vivo. We identified nonsynonymous mutations in 14 immediate NOTCH pathway genes affecting 24.1% and 16.8% of HCC patients in the two independent cohorts, respectively. Among these, the HES5-R31G mutation was predicted in silico to have high biological relevance. Functional analyses in cell culture showed that HES5 reduced cell migration and clonogenicity. Further analyses revealed that the patient-derived HES5-R31G mutant protein was non-functional due to loss of DNA binding and greatly reduced nuclear localization. Furthermore, HES5 exhibited a negative feedback loop by directly inhibiting the NOTCH target HES1 and downregulated the pro-proliferative MYC targets ODC1 and LDHA. Interestingly, HES5 inhibited MYC-dependent hepatocarcinogenesis, whereas it promoted AKT-dependent liver tumor formation and stem cell features in a murine model. Thus, NOTCH pathway component mutations are commonly observed in HCC. Furthermore, the NOTCH target gene HES5 has both pro- and anti-tumorigenic functions in liver cancer proposing a driver gene dependency and it promotes tumorigenesis with its interaction partner AKT.
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Affiliation(s)
- Sarah Luiken
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Angelika Fraas
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Bieg
- Center for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Berlin, Germany.,Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany
| | - Raisatun Sugiyanto
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Benjamin Goeppert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephan Singer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Carolin Ploeger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Gregor Warsow
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg, Germany
| | - Jens U Marquardt
- First Department of Medicine, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Carsten Sticht
- Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | | | - Stefan Pusch
- Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.,Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Norbert Gretz
- Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | - Matthias Schlesner
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg, Germany
| | - Roland Eils
- Center for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Berlin, Germany.,Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany.,Health Data Science Unit, University Hospital Heidelberg, Heidelberg, Germany.,Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
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41
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Bisso A, Sabò A, Amati B. MYC in Germinal Center-derived lymphomas: Mechanisms and therapeutic opportunities. Immunol Rev 2019; 288:178-197. [PMID: 30874346 DOI: 10.1111/imr.12734] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
The rearrangement of immunoglobulin loci during the germinal center reaction is associated with an increased risk of chromosomal translocations that activate oncogenes such as MYC, BCL2 or BCL6, thus contributing to the development of B-cell lymphomas. MYC and BCL2 activation are initiating events in Burkitt's (BL) and Follicular Lymphoma (FL), respectively, but can occur at later stages in other subtypes such as Diffuse Large-B Cell Lymphoma (DLBCL). MYC can also be activated during the progression of FL to the transformed stage. Thus, either DLBCL or FL can give rise to aggressive double-hit lymphomas (DHL) with concurrent activation of MYC and BCL2. Research over the last three decades has improved our understanding of the functions of these oncogenes and the basis for their cooperative action in lymphomagenesis. MYC, in particular, is a transcription factor that contributes to cell activation, growth and proliferation, while concomitantly sensitizing cells to apoptosis, the latter being blocked by BCL2. Here, we review our current knowledge about the role of MYC in germinal center B-cells and lymphomas, discuss MYC-induced dependencies that can sensitize cancer cells to select pharmacological inhibitors, and illustrate their therapeutic potential in aggressive lymphomas-and in particular in DHL, in combination with BCL2 inhibitors.
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Affiliation(s)
- Andrea Bisso
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Arianna Sabò
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Bruno Amati
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
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42
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Beielstein AC, Pallasch CP. Tumor Metabolism as a Regulator of Tumor-Host Interactions in the B-Cell Lymphoma Microenvironment-Fueling Progression and Novel Brakes for Therapy. Int J Mol Sci 2019; 20:E4158. [PMID: 31454887 PMCID: PMC6747254 DOI: 10.3390/ijms20174158] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 08/18/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022] Open
Abstract
Tumor metabolism and its specific alterations have become an integral part of understanding functional alterations leading to malignant transformation and maintaining cancer progression. Here, we review the metabolic changes in B-cell neoplasia, focusing on the effects of tumor metabolism on the tumor microenvironment (TME). Particularly, innate and adaptive immune responses are regulated by metabolites in the TME such as lactate. With steadily increasing therapeutic options implicating or utilizing the TME, it has become essential to address the metabolic alterations in B-cell malignancy for therapeutic approaches. In this review, we discuss metabolic alterations of B-cell lymphoma, consequences for currently used therapy regimens, and novel approaches specifically targeting metabolism in the TME.
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Affiliation(s)
- Anna C Beielstein
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Josef Stelzmann Street 24, 50937 Cologne, Germany
| | - Christian P Pallasch
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Josef Stelzmann Street 24, 50937 Cologne, Germany.
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43
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Ward NP, DeNicola GM. Sulfur metabolism and its contribution to malignancy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 347:39-103. [PMID: 31451216 DOI: 10.1016/bs.ircmb.2019.05.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Metabolic dysregulation is an appreciated hallmark of cancer and a target for therapeutic intervention. Cellular metabolism involves a series of oxidation/reduction (redox) reactions that yield the energy and biomass required for tumor growth. Cells require diverse molecular species with constituent sulfur atoms to facilitate these processes. For humans, this sulfur is derived from the dietary consumption of the proteinogenic amino acids cysteine and methionine, as only lower organisms (e.g., bacteria, fungi, and plants) can synthesize them de novo. In addition to providing the sulfur required to sustain redox chemistry, the metabolism of these sulfur-containing amino acids yield intermediate metabolites that constitute the cellular antioxidant system, mediate inter- and intracellular signaling, and facilitate the epigenetic regulation of gene expression, all of which contribute to tumorigenesis.
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Affiliation(s)
- Nathan P Ward
- Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Gina M DeNicola
- Department of Cancer Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
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44
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Polyamine Metabolism as a Therapeutic Target inHedgehog-Driven Basal Cell Carcinomaand Medulloblastoma. Cells 2019; 8:cells8020150. [PMID: 30754726 PMCID: PMC6406590 DOI: 10.3390/cells8020150] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/06/2019] [Accepted: 02/08/2019] [Indexed: 02/06/2023] Open
Abstract
Hedgehog (Hh) signaling is a critical developmental regulator and its aberrant activation,due to somatic or germline mutations of genes encoding pathway components, causes Basal CellCarcinoma (BCC) and medulloblastoma (MB). A growing effort has been devoted at theidentification of druggable vulnerabilities of the Hedgehog signaling, leading to the identificationof various compounds with variable efficacy and/or safety. Emerging evidence shows that anaberrant polyamine metabolism is a hallmark of Hh-dependent tumors and that itspharmacological inhibition elicits relevant therapeutic effects in clinical or preclinical models ofBCC and MB. We discuss here the current knowledge of polyamine metabolism, its role in cancerand the available targeting strategies. We review the literature about the connection betweenpolyamines and the Hedgehog signaling, and the potential therapeutic benefit of targetingpolyamine metabolism in two malignancies where Hh pathways play a well-established role: BCCand MB.
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45
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Li Y, Wang Y, Wu P. 5'-Methylthioadenosine and Cancer: old molecules, new understanding. J Cancer 2019; 10:927-936. [PMID: 30854099 PMCID: PMC6400808 DOI: 10.7150/jca.27160] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 12/17/2018] [Indexed: 12/19/2022] Open
Abstract
While the metabolic changes in cancer tissues were first observed by Warburg Otto almost a century ago, altered metabolism has recently returned as a focus of cancer research. 5'-Methylthioadenosine (MTA) is a naturally occurring sulfur-containing nucleoside found in numerous species. While MTA was first isolated several decades ago, a lack of sensitive and specific analytical methodologies designed for its direct quantification has hampered the study of its physiological and pathophysiological features. Many studies indicate that MTA suppresses tumors by inhibiting tumor cell proliferation, invasion, and the induction of apoptosis while controlling the inflammatory micro-environments of tumor tissue. In this review, we assessed the effects of MTA and of related materials on the growth and functions of normal and malignant cells.
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Affiliation(s)
- Yaofeng Li
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yubo Wang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Ping Wu
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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46
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Kielosto M, Eriksson J, Nummela P, Yin M, Hölttä E. Divergent roles of lysyl oxidase family members in ornithine decarboxylase- and RAS-transformed mouse fibroblasts and human melanoma cells. Oncotarget 2018; 9:37733-37752. [PMID: 30701028 PMCID: PMC6340875 DOI: 10.18632/oncotarget.26508] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 12/13/2018] [Indexed: 12/12/2022] Open
Abstract
We have previously shown that proto-oncoprotein c-Jun is activated in ornithine decarboxylase (ODC)- and RAS-transformed mouse fibroblasts, and that the transformed morphology of these cells can be reversed by expressing the transactivation domain deletion mutant of c-Jun (TAM67). Here, we found that lysyl oxidase (Lox), encoding an extracellular matrix-modifying enzyme, is downregulated in a c-Jun-dependent manner in ODC-transformed fibroblasts (Odc cells). In addition to Lox, the Lox family members Lox-like 1 and 3 (Loxl1 and Loxl3) were found to be downregulated in Odc as well as in RAS-transformed fibroblasts (E4), whereas Lox-like 4 (Loxl4) was upregulated in Odc and downregulated in E4 cells compared to normal N1 fibroblasts. Tetracycline-regulatable LOX re-expression in Odc cells led to inhibition of cell growth and invasion in three-dimensional Matrigel in an activity-independent manner. On the contrary, LOX and especially LOXL2, LOXL3, and LOXL4 were found to be upregulated in several human melanoma cell lines, and LOX inhibitor B-aminopropionitrile inhibited the invasive growth of these cells particularly when co-cultured with fibroblasts in Matrigel. Knocking down the expression of LOX and especially LOXL2 in melanoma cells almost completely abrogated the invasive growth capability. Further, LOXL2 was significantly upregulated in clinical human primary melanomas compared to benign nevi, and high expression of LOXL2 in primary melanomas was associated with formation of metastases and shorter survival of patients. Thus, our studies reveal that inactive pro-LOX (together with Lox propeptide) functions as a tumor suppressor in ODC- and RAS-transformed murine fibroblasts by inhibiting cell growth and invasion, and active LOX and LOXL2 as tumor promoters in human melanoma cells by promoting their invasive growth.
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Affiliation(s)
- Mari Kielosto
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Johanna Eriksson
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Pirjo Nummela
- Department of Pathology, University of Helsinki, Helsinki, Finland.,Current address: University of Helsinki, Genome-Scale Biology Research Program, Helsinki, Finland
| | - Miao Yin
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Erkki Hölttä
- Department of Pathology, University of Helsinki, Helsinki, Finland
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Razvi SS, Choudhry H, Hasan MN, Hassan MA, Moselhy SS, Abualnaja KO, Zamzami MA, Kumosani TA, Al-Malki AL, Halwani MA, Ibrahim A, Hamiche A, Bronner C, Asami T, Alhosin M. Identification of Deregulated Signaling Pathways in Jurkat Cells in Response to a Novel Acylspermidine Analogue-N 4-Erucoyl Spermidine. Epigenet Insights 2018; 11:2516865718814543. [PMID: 30515476 PMCID: PMC6262497 DOI: 10.1177/2516865718814543] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 10/29/2018] [Indexed: 12/25/2022] Open
Abstract
Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N4-Erucoyl spermidine (designed as N4-Eru), a novel acylspermidine derivative, has been shown to exert selective inhibitory effects on both hematological and solid tumors, but its mechanisms of action are unknown. In this study, RNA sequencing was performed to investigate the anticancer mechanisms of N4-Eru-treated T-cell acute lymphoblastic leukemia (ALL) cell line (Jurkat cells), and gene expression was examined through different tools. We could show that many key oncogenes including NDRG1, CACNA1G, TGFBR2, NOTCH1,2,3, UHRF1, DNMT1,3, HDAC1,3, KDM3A, KDM4B, KDM4C, FOS, and SATB1 were downregulated, whereas several tumor suppressor genes such as CDKN2AIPNL, KISS1, DDIT3, TP53I13, PPARG, FOXP1 were upregulated. Data obtained through RNA-Seq further showed that N4-Eru inhibited the NOTCH/Wnt/JAK-STAT axis. This study also indicated that N4-Eru-induced apoptosis could involve several key signaling pathways in cancer. Altogether, our results suggest that N4-Eru is a promising drug to treat ALL.
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Affiliation(s)
- Syed Shoeb Razvi
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hani Choudhry
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Nihal Hasan
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed A Hassan
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Basic Medical Sciences, College of Medicine and Health Sciences, Hadhramout University, Mukalla, Yemen
| | - Said Salama Moselhy
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Bioactive Natural Products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.,Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Khalid Omer Abualnaja
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Bioactive Natural Products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazin A Zamzami
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Taha Abduallah Kumosani
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Production of Bioproducts for Industrial Applications Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulrahman Labeed Al-Malki
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Bioactive Natural Products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Majed A Halwani
- Nanomedicine Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdulkhaleg Ibrahim
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258 CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Ali Hamiche
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258 CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Christian Bronner
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258 CNRS UMR 7104, Université de Strasbourg, Illkirch, France
| | - Tadao Asami
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Mahmoud Alhosin
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer Metabolism and Epigenetic Unit, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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Abstract
This paper is in recognition of the 100th birthday of Dr. Herbert Tabor, a true pioneer in the polyamine field for over 70 years, who served as the editor-in-chief of the Journal of Biological Chemistry from 1971 to 2010. We review current knowledge of MYC proteins (c-MYC, MYCN, and MYCL) and focus on ornithine decarboxylase 1 (ODC1), an important bona fide gene target of MYC, which encodes the sentinel, rate-limiting enzyme in polyamine biosynthesis. Although notable advances have been made in designing inhibitors against the "undruggable" MYCs, their downstream targets and pathways are currently the main avenue for therapeutic anticancer interventions. To this end, the MYC-ODC axis presents an attractive target for managing cancers such as neuroblastoma, a pediatric malignancy in which MYCN gene amplification correlates with poor prognosis and high-risk disease. ODC and polyamine levels are often up-regulated and contribute to tumor hyperproliferation, especially of MYC-driven cancers. We therefore had proposed to repurpose α-difluoromethylornithine (DFMO), an FDA-approved, orally available ODC inhibitor, for management of neuroblastoma, and this intervention is now being pursued in several clinical trials. We discuss the regulation of ODC and polyamines, which besides their well-known interactions with DNA and tRNA/rRNA, are involved in regulating RNA transcription and translation, ribosome function, proteasomal degradation, the circadian clock, and immunity, events that are also controlled by MYC proteins.
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Affiliation(s)
- André S Bachmann
- From the Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan 49503 and
| | - Dirk Geerts
- the Department of Medical Biology, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Pegg AE. Introduction to the Thematic Minireview Series: Sixty plus years of polyamine research. J Biol Chem 2018; 293:18681-18692. [PMID: 30377254 DOI: 10.1074/jbc.tm118.006291] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Polyamines have a long history in biochemistry and physiology, dating back to 1678 when Leeuwenhoek first reported crystals that were composed of spermine phosphate in seminal fluid. Their quantification and biosynthetic pathway were first described by Herb and Celia Tabor in collaboration with Sanford Rosenthal in the late 1950s. This work led to immense interest in their physiological functions. The 11 Minireviews in this collection illustrate many of the wide-ranging biochemical effects of the polyamines. This series provides a fitting tribute to Herb Tabor on the occasion of his 100th birthday, demonstrating clearly the importance and growth of the research field that he pioneered in the late 1950s and has contributed to for many years. His studies of the synthesis, function, and toxicity of polyamines have yielded multiple insights into fundamental biochemical processes and formed the basis of successful and continuing drug development. This Minireview series reviews the highly diverse properties of polyamines in bacteria, protozoa, and mammals, highlighting the importance of these molecules in growth, development, and response to the environment, and their involvement in diseases, including cancer, and those caused by parasitic protozoans.
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Affiliation(s)
- Anthony E Pegg
- From the Departments of Cellular and Molecular Physiology and of Pharmacology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033
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50
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Myc, Oncogenic Protein Translation, and the Role of Polyamines. Med Sci (Basel) 2018; 6:medsci6020041. [PMID: 29799508 PMCID: PMC6024823 DOI: 10.3390/medsci6020041] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/19/2018] [Accepted: 05/22/2018] [Indexed: 01/21/2023] Open
Abstract
Deregulated protein synthesis is a common feature of cancer cells, with many oncogenic signaling pathways directly augmenting protein translation to support the biomass needs of proliferating tissues. MYC’s ability to drive oncogenesis is a consequence of its essential role as a governor linking cell cycle entry with the requisite increase in protein synthetic capacity, among other biomass needs. To date, direct pharmacologic inhibition of MYC has proven difficult, but targeting oncogenic signaling modules downstream of MYC, such as the protein synthetic machinery, may provide a viable therapeutic strategy. Polyamines are essential cations found in nearly all living organisms that have both direct and indirect roles in the control of protein synthesis. Polyamine metabolism is coordinately regulated by MYC to increase polyamines in proliferative tissues, and this is further augmented in the many cancer cells harboring hyperactivated MYC. In this review, we discuss MYC-driven regulation of polyamines and protein synthetic capacity as a key function of its oncogenic output, and how this dependency may be perturbed through direct pharmacologic targeting of components of the protein synthetic machinery, such as the polyamines themselves, the eukaryotic translation initiation factor 4F (eIF4F) complex, and the eukaryotic translation initiation factor 5A (eIF5A).
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