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Glorieux C, Enríquez C, Buc Calderon P. The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment. Biochem Pharmacol 2025; 232:116729. [PMID: 39709038 DOI: 10.1016/j.bcp.2024.116729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/09/2024] [Accepted: 12/19/2024] [Indexed: 12/23/2024]
Abstract
The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS). On the one hand, ROS can inhibit or activate mTOR pathway in cancer cells through various mechanisms. Conversely, mTOR signaling can induce oxidative stress in tumor cells notably due to the inhibition in the expression of antioxidant enzyme genes. Since mTOR is often activated and plays crucial role in cancer cell survival, the use of mTOR inhibitors, which often induce ROS accumulation, could be an interesting approach for cancer treatment. This review will address the advantages, disadvantages, combination strategies, and limitations associated with therapeutic modulation of mTOR signaling pathway in cancer treatment.
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Affiliation(s)
- Christophe Glorieux
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 510060 Guangzhou, China.
| | - Cinthya Enríquez
- Química y Farmacia, Facultad de Ciencias de la Salud, Universidad Arturo Prat, 1100000 Iquique, Chile; Programa de Doctorado en Química Medicinal, Facultad de Ciencias de la Salud, Universidad Arturo Prat, 1100000 Iquique, Chile
| | - Pedro Buc Calderon
- Química y Farmacia, Facultad de Ciencias de la Salud, Universidad Arturo Prat, 1100000 Iquique, Chile; Instituto de Química Medicinal, Universidad Arturo Prat, 1100000 Iquique, Chile; Research Group in Metabolism and Nutrition, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
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2
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Drewa J, Lazar-Juszczak K, Adamowicz J, Juszczak K. Periprostatic Adipose Tissue as a Contributor to Prostate Cancer Pathogenesis: A Narrative Review. Cancers (Basel) 2025; 17:372. [PMID: 39941741 PMCID: PMC11816168 DOI: 10.3390/cancers17030372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/03/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Periprostatic adipose tissue (PPAT) contributes to the pathogenesis of prostate cancer. The purpose of this study was to review and summarize the literature on the role of PPAT in prostate cancer pathogenesis. Moreover, we evaluated the clinical implication of PPAT in patients with prostate cancer. We performed a scoping literature review of PubMed from January 2002 to November 2024. Search terms included "periprostatic adipose tissue", "adipokines", and "prostate cancer". Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included PPAT, adipokines, and their role in prostate cancer biology and clinical features. In total 225 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the pathogenesis of PPAT as a contributor to prostate cancer biology and its aggressiveness. The review also presents new research directions for PPAT as a new target for the treatment of prostate cancer. Based on the current review, it can be stated that PPAT plays an important role in prostate cancer pathogenesis. Moreover, PPAT seems to be a promising target point when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer.
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Affiliation(s)
- Julia Drewa
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
| | - Katarzyna Lazar-Juszczak
- Primary Health Care Clinic of the Ujastek Medical Center, 31-752 Cracow, Poland
- Krakow University of Health Promotion, 31-158 Cracow, Poland
| | - Jan Adamowicz
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
- Department of Regenerative Medicine, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
| | - Kajetan Juszczak
- Department of Urology and Andrology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland
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3
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Yao P, Cao S, Zhu Z, Wen Y, Guo Y, Liang W, Xie J. Cellular Signaling of Amino Acid Metabolism in Prostate Cancer. Int J Mol Sci 2025; 26:776. [PMID: 39859489 PMCID: PMC11765784 DOI: 10.3390/ijms26020776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/30/2025] Open
Abstract
Prostate cancer is one of the most common malignancies affecting men worldwide and a leading cause of cancer-related mortality, necessitating a deeper understanding of its underlying biochemical pathways. Similar to other cancer types, prostate cancer is also characterised by aberrantly activated metabolic pathways that support tumour development, such as amino acid metabolism, which is involved in modulating key physiological and pathological cellular processes during the progression of this disease. The metabolism of several amino acids, such as glutamine and methionine, crucial for tumorigenesis, is dysregulated and commonly discussed in prostate cancer. And the roles of some less studied amino acids, such as histidine and glycine, have also been covered in prostate cancer studies. Aberrant regulation of two major signalling pathways, mechanistic target of rapamycin (mTOR) and general amino acid control non-depressible 2 (GCN2), is a key driver of reshaping the amino acid metabolism landscape in prostate cancer. By summarising our current understanding of how amino acid metabolism is modulated in prostate cancer, here, we provide further insights into certain potential therapeutic targets for managing prostate cancer through metabolic interventions.
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Affiliation(s)
- Ping Yao
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Shiqi Cao
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Ziang Zhu
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Yunru Wen
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Yawen Guo
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Wenken Liang
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
| | - Jianling Xie
- School of Biology and Biological Engineering, South China University of Technology, University Town, Guangzhou 510006, China
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia
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4
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Bakht MK, Beltran H. Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer. Nat Rev Urol 2025; 22:26-45. [PMID: 38977769 PMCID: PMC11841200 DOI: 10.1038/s41585-024-00900-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2024] [Indexed: 07/10/2024]
Abstract
Prostate-specific membrane antigen (PSMA) is an important cell-surface imaging biomarker and therapeutic target in prostate cancer. The PSMA-targeted theranostic 177Lu-PSMA-617 was approved in 2022 for men with PSMA-PET-positive metastatic castration-resistant prostate cancer. However, not all patients respond to PSMA-radioligand therapy, in part owing to the heterogeneity of PSMA expression in the tumour. The PSMA regulatory network is composed of a PSMA transcription complex, an upstream enhancer that loops to the FOLH1 (PSMA) gene promoter, intergenic enhancers and differentially methylated regions. Our understanding of the PSMA regulatory network and the mechanisms underlying PSMA suppression is evolving. Clinically, molecular imaging provides a unique window into PSMA dynamics that occur on therapy and with disease progression, although challenges arise owing to the limited resolution of PET. PSMA regulation and heterogeneity - including intertumoural and inter-patient heterogeneity, temporal changes, lineage dynamics and the tumour microenvironment - affect PSMA theranostics. PSMA response and resistance to radioligand therapy are mediated by a number of potential mechanisms, and complementary biomarkers beyond PSMA are under development. Understanding the biological determinants of cell surface target regulation and heterogeneity can inform precision medicine approaches to PSMA theranostics as well as other emerging therapies.
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Affiliation(s)
- Martin K Bakht
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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Erb HHH, Polishchuk N, Stasyk O, Kahya U, Weigel MM, Dubrovska A. Glutamine Metabolism and Prostate Cancer. Cancers (Basel) 2024; 16:2871. [PMID: 39199642 PMCID: PMC11352381 DOI: 10.3390/cancers16162871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 09/01/2024] Open
Abstract
Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials.
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Affiliation(s)
- Holger H. H. Erb
- Department of Urology, Technische Universität Dresden, 01307 Dresden, Germany;
| | - Nikita Polishchuk
- Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, 79000 Lviv, Ukraine; (N.P.); (O.S.)
| | - Oleh Stasyk
- Department of Cell Signaling, Institute of Cell Biology, National Academy of Sciences of Ukraine, 79000 Lviv, Ukraine; (N.P.); (O.S.)
| | - Uğur Kahya
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (M.M.W.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
| | - Matthias M. Weigel
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (M.M.W.)
| | - Anna Dubrovska
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (M.M.W.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, 01309 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany
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Tamarindo GH, Ribeiro CF, Silva ADT, Castro A, Caruso ÍP, Souza FP, Taboga SR, Loda M, Góes RM. The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells. Cancer Metab 2024; 12:24. [PMID: 39113152 PMCID: PMC11308158 DOI: 10.1186/s40170-024-00348-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 06/29/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines. METHODS Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [14C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, 1H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation. RESULTS In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1. CONCLUSION In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.
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Affiliation(s)
- Guilherme Henrique Tamarindo
- Institute of Biology, State University of Campinas, Campinas, São Paulo, Brazil
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, São Paulo, Brazil
| | | | - Alana Della Torre Silva
- Department of Biological Sciences, IBILCE - UNESP. Rua Cristovão Colombo, 2265 Jardim Nazareth, São José Do Rio Preto, São Paulo, 15054-000, Brazil
| | - Alex Castro
- Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, São Paulo, Brazil
| | - Ícaro Putinhon Caruso
- Department of Biophysics, Institute of Biosciences, Humanities and Exact Science, São Paulo State University, São José Do Rio Preto, São Paulo, Brazil
- Institute of Medical Biochemistry and National Center for Structure Biology and Bioimaging (CENABIO), National Center for Nuclear Magnetic Resonance of Macromolecules, Federal University of Rio de Janeiro, Ilha Do Fundão, Rio de Janeiro, Brazil
| | - Fátima Pereira Souza
- Department of Biophysics, Institute of Biosciences, Humanities and Exact Science, São Paulo State University, São José Do Rio Preto, São Paulo, Brazil
| | - Sebastião Roberto Taboga
- Department of Biological Sciences, IBILCE - UNESP. Rua Cristovão Colombo, 2265 Jardim Nazareth, São José Do Rio Preto, São Paulo, 15054-000, Brazil
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Rejane Maira Góes
- Department of Biological Sciences, IBILCE - UNESP. Rua Cristovão Colombo, 2265 Jardim Nazareth, São José Do Rio Preto, São Paulo, 15054-000, Brazil.
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7
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Li D, Min Z, Guo J, Chen Y, Zhang W. ExpOmics: a comprehensive web platform empowering biologists with robust multi-omics data analysis capabilities. Bioinformatics 2024; 40:btae507. [PMID: 39128019 PMCID: PMC11343375 DOI: 10.1093/bioinformatics/btae507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/18/2024] [Accepted: 08/09/2024] [Indexed: 08/13/2024] Open
Abstract
MOTIVATION High-throughput technologies yield a broad spectrum of multi-omics datasets, which offer unparalleled insights into complex biological systems. However, effectively analyzing this diverse array of data presents challenges, considering factors such as species diversity, data types, costs, and limitations of the available tools. RESULTS Herein, we present ExpOmics, a comprehensive web platform featuring 7 applications and 4 toolkits, with 28 customizable analysis functions spanning various analyses of differential expression, co-expression, Weighted Gene Co-expression Network Analysis (WGCNA), feature selection, and functional enrichment. ExpOmics allows users to upload and explore multi-omics data without organism restrictions, supporting various expression data, including genes, mRNAs, lncRNAs, miRNAs, circRNAs, piRNAs, and proteins and is compatible with diverse gene nomenclatures and expression values. Moreover, ExpOmics enables users to analyze 22 427 transcriptomic datasets of 196 cancer subtypes sourced from 63 projects of The Cancer Genome Atlas Program (TCGA) to identify cancer biomarkers. The analysis results from ExpOmics are presented in high-quality graphical formats suitable for publication and are available for free download. A case study using ExpOmics identified two potential oncogenes, SERPINE1 and SLC43A1, that may regulate colorectal cancer through distinct biological processes. In summary, ExpOmics can serves as a robust platform for global researchers to explore multi-omics data, gain biological insights, and formulate testable hypotheses. AVAILABILITY AND IMPLEMENTATION ExpOmics is available at http://www.biomedical-web.com/expomics.
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Affiliation(s)
- Douyue Li
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China
| | - Zhuochao Min
- School of Zoology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Jia Guo
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China
| | - Yubin Chen
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China
| | - Wenliang Zhang
- The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University, GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, People’s Republic of China
- Department of Bioinformatics, Outstanding Biotechnology Co., Ltd-Shenzhen, Shenzhen 518026, People’s Republic of China
- Department of Pediatrics, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, People’s Republic of China
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Saito S, Ando K, Sakamoto S, Xu M, Yamada Y, Rii J, Kanaoka S, Wei J, Zhao X, Pae S, Kanesaka M, Goto Y, Sazuka T, Imamura Y, Reien Y, Hamaguchi-Suzuki N, Saito S, Hirayama Y, Hashimoto H, Kanai Y, Ichikawa T, Anzai N. The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism. Cancer Sci 2024; 115:2461-2472. [PMID: 38655663 PMCID: PMC11247547 DOI: 10.1111/cas.16191] [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: 10/12/2023] [Revised: 03/27/2024] [Accepted: 04/08/2024] [Indexed: 04/26/2024] Open
Abstract
L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/β-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.
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Affiliation(s)
- Shinpei Saito
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Keisuke Ando
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinichi Sakamoto
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Minhui Xu
- Bio-System Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasutaka Yamada
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Junryo Rii
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Sanji Kanaoka
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Jiaxing Wei
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Xue Zhao
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Sangjon Pae
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Manato Kanesaka
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yusuke Goto
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomokazu Sazuka
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yusuke Imamura
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yoshie Reien
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | | | - Shota Saito
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuri Hirayama
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hirofumi Hashimoto
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yoshikatsu Kanai
- Bio-System Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomohiko Ichikawa
- Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Naohiko Anzai
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
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9
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Krieg S, Fernandes SI, Kolliopoulos C, Liu M, Fendt SM. Metabolic Signaling in Cancer Metastasis. Cancer Discov 2024; 14:934-952. [PMID: 38592405 PMCID: PMC7616057 DOI: 10.1158/2159-8290.cd-24-0174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 04/10/2024]
Abstract
Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein-protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis. SIGNIFICANCE Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.
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Affiliation(s)
- Sarah Krieg
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
| | - Sara Isabel Fernandes
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
| | - Constantinos Kolliopoulos
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
| | - Ming Liu
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium
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10
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Egbujor MC, Olaniyan OT, Emeruwa CN, Saha S, Saso L, Tucci P. An insight into role of amino acids as antioxidants via NRF2 activation. Amino Acids 2024; 56:23. [PMID: 38506925 PMCID: PMC10954862 DOI: 10.1007/s00726-024-03384-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/31/2024] [Indexed: 03/22/2024]
Abstract
Oxidative stress can affect the protein, lipids, and DNA of the cells and thus, play a crucial role in several pathophysiological conditions. It has already been established that oxidative stress has a close association with inflammation via nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. Amino acids are notably the building block of proteins and constitute the major class of nitrogen-containing natural products of medicinal importance. They exhibit a broad spectrum of biological activities, including the ability to activate NRF2, a transcription factor that regulates endogenous antioxidant responses. Moreover, amino acids may act as synergistic antioxidants as part of our dietary supplementations. This has aroused research interest in the NRF2-inducing activity of amino acids. Interestingly, amino acids' activation of NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signaling pathway exerts therapeutic effects in several diseases. Therefore, the present review will discuss the relationship between different amino acids and activation of NRF2-KEAP1 signaling pathway pinning their anti-inflammatory and antioxidant properties. We also discussed amino acids formulations and their applications as therapeutics. This will broaden the prospect of the therapeutic applications of amino acids in a myriad of inflammation and oxidative stress-related diseases. This will provide an insight for designing and developing new chemical entities as NRF2 activators.
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Affiliation(s)
- Melford C Egbujor
- Department of Chemistry, Federal University Otuoke, Otuoke, Bayelsa, Nigeria
| | | | | | - Sarmistha Saha
- Department of Biotechnology, Institute of Applied Sciences and Humanities, GLA University, Mathura, 281406, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Vittorio Erspamer, Sapienza University of Rome, 00161, Rome, Italy.
| | - Paolo Tucci
- Department of Clinical and Experimental Medicine, University of Foggia, 71122, Foggia, Italy
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11
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Chen J, Cui L, Lu S, Xu S. Amino acid metabolism in tumor biology and therapy. Cell Death Dis 2024; 15:42. [PMID: 38218942 PMCID: PMC10787762 DOI: 10.1038/s41419-024-06435-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/19/2023] [Accepted: 01/04/2024] [Indexed: 01/15/2024]
Abstract
Amino acid metabolism plays important roles in tumor biology and tumor therapy. Accumulating evidence has shown that amino acids contribute to tumorigenesis and tumor immunity by acting as nutrients, signaling molecules, and could also regulate gene transcription and epigenetic modification. Therefore, targeting amino acid metabolism will provide new ideas for tumor treatment and become an important therapeutic approach after surgery, radiotherapy, and chemotherapy. In this review, we systematically summarize the recent progress of amino acid metabolism in malignancy and their interaction with signal pathways as well as their effect on tumor microenvironment and epigenetic modification. Collectively, we also highlight the potential therapeutic application and future expectation.
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Affiliation(s)
- Jie Chen
- National Key Lab of Immunity and Inflammation and Institute of Immunology, Naval Medical University/Second Military Medical University, Shanghai, 200433, China
| | - Likun Cui
- National Key Lab of Immunity and Inflammation and Institute of Immunology, Naval Medical University/Second Military Medical University, Shanghai, 200433, China
| | - Shaoteng Lu
- National Key Lab of Immunity and Inflammation and Institute of Immunology, Naval Medical University/Second Military Medical University, Shanghai, 200433, China
| | - Sheng Xu
- National Key Lab of Immunity and Inflammation and Institute of Immunology, Naval Medical University/Second Military Medical University, Shanghai, 200433, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
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12
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Tae K, Kim SJ, Cho SW, Lee H, Cha HS, Choi CY. L-Type Amino Acid Transporter 1 (LAT1) Promotes PMA-Induced Cell Migration through mTORC2 Activation at the Lysosome. Cells 2023; 12:2504. [PMID: 37887348 PMCID: PMC10605051 DOI: 10.3390/cells12202504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/17/2023] [Accepted: 10/20/2023] [Indexed: 10/28/2023] Open
Abstract
The mTOR signaling pathway integrates signaling inputs from nutrients, including glucose and amino acids, which are precisely regulated by transporters depending on nutrient levels. The L-type amino acid transporter 1 (LAT1) affects the activity of mTORC1 through upstream regulators that sense intracellular amino acid levels. While mTORC1 activation by LAT1 has been thoroughly investigated in cultured cells, the effects of LAT1 expression on the activity of mTORC2 has scarcely been studied. Here, we provide evidence that LAT1 recruits and activates mTORC2 on the lysosome for PMA-induced cell migration. LAT1 is translocated to the lysosomes in cells treated with PMA in a dose- and time-dependent manner. Lysosomal LAT1 interacted with mTORC2 through a direct interaction with Rictor, leading to the lysosomal localization of mTORC2. Furthermore, the depletion of LAT1 reduced PMA-induced cell migration in a wound-healing assay. Consistent with these results, the LAT1 N3KR mutant, which is defective in PMA-induced endocytosis and lysosomal localization, did not induce mTORC2 recruitment to the lysosome, with the activation of mTORC2 determined via Akt phosphorylation or the LAT1-mediated promotion of cell migration. Taken together, lysosomal LAT1 recruits and activates the mTORC2 complex and downstream Akt for PMA-mediated cell migration. These results provide insights into the development of therapeutic drugs targeting the LAT1 amino acid transporter to block metastasis, as well as disease progression in various types of cancer.
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Affiliation(s)
| | | | | | | | | | - Cheol-Yong Choi
- Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea; (K.T.); (S.-J.K.); (S.-W.C.); (H.L.); (H.-S.C.)
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13
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Xia P, Dubrovska A. CD98 heavy chain as a prognostic biomarker and target for cancer treatment. Front Oncol 2023; 13:1251100. [PMID: 37823053 PMCID: PMC10562705 DOI: 10.3389/fonc.2023.1251100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/29/2023] [Indexed: 10/13/2023] Open
Abstract
The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y+LAT1 (SLC7A7), y+LAT2 (SLC7A6), xCT (SLC7A11) and Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake. In this way, CD98hc connects the signaling pathways sustaining cell proliferation and migration, biosynthesis and antioxidant defense, energy production, and stem cell properties. This multifaceted role makes CD98hc one of the critical regulators of tumor growth, therapy resistance, and metastases. Indeed, the high expression levels of CD98hc were confirmed in various tumor tissues, including head and neck squamous cell carcinoma, glioblastoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and others. A high expression of CD98hc has been linked to clinical prognosis and response to chemo- and radiotherapy in several types of cancer. In this mini-review, we discuss the physiological functions of CD98hc, its role in regulating tumor stemness, metastases, and therapy resistance, and the clinical significance of CD98hc as a tumor marker and therapeutic target.
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Affiliation(s)
- Pu Xia
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Anna Dubrovska
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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14
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Xian F, Zhao C, Huang C, Bie J, Xu G. The potential role of CDC20 in tumorigenesis, cancer progression and therapy: A narrative review. Medicine (Baltimore) 2023; 102:e35038. [PMID: 37682144 PMCID: PMC10489547 DOI: 10.1097/md.0000000000035038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/11/2023] [Indexed: 09/09/2023] Open
Abstract
The cell division cycle 20 homologue (CDC20) is known to regulate the cell cycle. Many studies have suggested that dysregulation of CDC20 is associated with various pathological processes in malignant solid tumors, including tumorigenesis, progression, chemoradiotherapy resistance, and poor prognosis, providing a biomarker for cancer diagnosis and prognosis. Some researchers have demonstrated that CDC20 also regulates apoptosis, immune microenvironment, and tumor angiogenesis. In this review, we have systematically summarized the biological functions of CDC20 in solid cancers. Furthermore, we briefly synthesized multiple medicines that inhibited CDC20. We anticipate that CDC20 will be a promising and effective biomarker and therapeutic target for the treatment of human cancer.
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Affiliation(s)
- Feng Xian
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Oncology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, China
| | - Caixia Zhao
- Department of Oncology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, China
| | - Chun Huang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Bie
- Department of Oncology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, China
| | - Guohui Xu
- Department of Interventional Radiology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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15
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Yurttas AG, Okat Z, Elgun T, Cifci KU, Sevim AM, Gul A. Genetic deviation associated with photodynamic therapy in HeLa cell. Photodiagnosis Photodyn Ther 2023; 42:103346. [PMID: 36809810 DOI: 10.1016/j.pdpdt.2023.103346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/05/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023]
Abstract
Photodynamic therapy (PDT) is a method that is used in cancer treatment. The main therapeutic effect is the production of singlet oxygen (1O2). Phthalocyanines for PDT produce high singlet oxygen with absorbers of about 600-700 nm. AIM It is aimed to analyze cancer cell pathways by flow cytometry analysis and cancer-related genes with q-PCR device by applying phthalocyanine L1ZnPC, which we use as photosensitizer in photodynamic therapy, in HELA cell line. In this study, we investigate the molecular basis of L1ZnPC's anti-cancer activity. MATERIAL METHOD The cytotoxic effects of L1ZnPC, a phthalocyanine obtained from our previous study, in HELA cells were evaluated and it was determined that it led to a high rate of death as a result. The result of photodynamic therapy was analyzed using q-PCR. From the data received at the conclusion of this investigation, gene expression values were calculated, and expression levels were assessed using the 2-∆∆Ct method to examine the relative changes in these values. Cell death pathways were interpreted with the FLOW cytometer device. One-Way Analysis of Variance (ANOVA) and the Tukey-Kramer Multiple Comparison Test with Post-hoc Test were used for the statistical analysis. CONCLUSION In our study, it was observed that HELA cancer cells underwent apoptosis at a rate of 80% with drug application plus photodynamic therapy by flow cytometry method. According to q-PCR results, CT values of eight out of eighty-four genes were found to be significant and their association with cancer was evaluated. L1ZnPC is a new phthalocyanine used in this study and our findings should be supported by further studies. For this reason, different analyses are needed to be performed with this drug in different cancer cell lines. In conclusion, according to our results, this drug looks promising but still needs to be analyzed through new studies. It is necessary to examine in detail which signaling pathways they use and their mechanism of action. For this, additional experiments are required.
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Affiliation(s)
- Asiye Gok Yurttas
- Department of Biochemistry, Faculty of Pharmacy, Istanbul Health and Technology University, Istanbul, Turkey.
| | - Zehra Okat
- Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Tugba Elgun
- Medical Biology, Faculty of Medicine, Istanbul Biruni University, Istanbul, Turkey
| | - Kezban Ucar Cifci
- Division of Basic Sciences and Health, Hemp Research Institute, Yozgat Bozok University, Yozgat, Turkey; Department of Molecular Medicine, Institute of Health Sciences, University of Health Sciences, Turkey
| | - Altug Mert Sevim
- Department of Chemistry, Istanbul Technical University, Istanbul, Turkey
| | - Ahmet Gul
- Department of Chemistry, Istanbul Technical University, Istanbul, Turkey
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16
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Kim SY, Ong Q, Liao Y, Ding Z, Tan AQL, Lim LTR, Tan HM, Lim SL, Lee QY, Han W. Genetic Ablation of LAT1 Inhibits Growth of Liver Cancer Cells and Downregulates mTORC1 Signaling. Int J Mol Sci 2023; 24:ijms24119171. [PMID: 37298123 DOI: 10.3390/ijms24119171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023] Open
Abstract
Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer.
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Affiliation(s)
- Sun-Yee Kim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Qunxiang Ong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Yilie Liao
- Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore
| | - Zhaobing Ding
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Alicia Qian Ler Tan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Ler Ting Rachel Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Hui Min Tan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Siew Lan Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Qian Yi Lee
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
| | - Weiping Han
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #02-02, Helios, Singapore 138667, Singapore
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17
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Zhao X, Sakamoto S, Wei J, Pae S, Saito S, Sazuka T, Imamura Y, Anzai N, Ichikawa T. Contribution of the L-Type Amino Acid Transporter Family in the Diagnosis and Treatment of Prostate Cancer. Int J Mol Sci 2023; 24:ijms24076178. [PMID: 37047148 PMCID: PMC10094571 DOI: 10.3390/ijms24076178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
The L-type amino acid transporter (LAT) family contains four members, LAT1~4, which are important amino acid transporters. They mainly transport specific amino acids through cell membranes, provide nutrients to cells, and are involved in a variety of metabolic pathways. They regulate the mTOR signaling pathway which has been found to be strongly linked to cancer in recent years. However, in the field of prostate cancer (PCa), the LAT family is still in the nascent stage of research, and the importance of LATs in the diagnosis and treatment of prostate cancer is still unknown. Therefore, this article aims to report the role of LATs in prostate cancer and their clinical significance and application. LATs promote the progression of prostate cancer by increasing amino acid uptake, activating the mammalian target of rapamycin (mTOR) pathway and downstream signals, mediating castration-resistance, promoting tumor angiogenesis, and enhancing chemotherapy resistance. The importance of LATs as diagnostic and therapeutic targets for prostate cancer was emphasized and the latest research results were introduced. In addition, we introduced selective LAT1 inhibitors, including JPH203 and OKY034, which showed excellent inhibitory effects on the proliferation of various tumor cells. This is the future direction of amino acid transporter targeting therapy drugs.
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Affiliation(s)
- Xue Zhao
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shinichi Sakamoto
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Jiaxing Wei
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Sangjon Pae
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shinpei Saito
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomokazu Sazuka
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yusuke Imamura
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Naohiko Anzai
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomohiko Ichikawa
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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18
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Yu M, Zhang S. Influenced tumor microenvironment and tumor immunity by amino acids. Front Immunol 2023; 14:1118448. [PMID: 36798123 PMCID: PMC9927402 DOI: 10.3389/fimmu.2023.1118448] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 01/19/2023] [Indexed: 02/03/2023] Open
Abstract
It is widely accepted that tumors are a complex tissue composed of cancer cells, extracellular matrix, inflammatory cells, immune cells, and other cells. Deregulation of tumor microenvironment promotes tumor aggressiveness by sustaining cell growth, invasion, and survival from immune surveillance. The concepts that some dietary nutrients could change tumor microenvironment are extremely attractive. Many studies demonstrated that high-fat diet-induced obesity shaped metabolism to suppress anti-tumor immunity, but how amino acids changed the tumor microenvironment and impacted tumor immunity was still not totally understood. In fact, amino acid metabolism in different signaling pathways and their cross-talk shaped tumor immunity and therapy efficacy in cancer patients. Our review focused on mechanisms by which amino acid influenced tumor microenvironment, and found potential drug targets for immunotherapy in cancer.
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Affiliation(s)
- Min Yu
- Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shuang Zhang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Sichuan, Chengdu, China,*Correspondence: Shuang Zhang,
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19
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Bhowmick N, Posadas E, Ellis L, Freedland SJ, Di Vizio D, Freeman MR, Theodorescu D, Figlin R, Gong J. Targeting Glutamine Metabolism in Prostate Cancer. Front Biosci (Elite Ed) 2023; 15:2. [PMID: 36959101 PMCID: PMC11983434 DOI: 10.31083/j.fbe1501002] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/25/2022] [Accepted: 07/05/2022] [Indexed: 01/10/2023]
Abstract
Glutamine is a conditionally essential amino acid important for cancer cell proliferation through intermediary metabolism leading to de novo synthesis of purine and pyrimidine nucleotides, hexosamine biosytnehsis, fatty acid synthesis through reductive carboxylation, maintenance of redox homeostasis, glutathione synthesis, production of non-essential amino acids, and mitochondrial oxidative phosphorylation. Prostate cancer has increasingly been characterized as a tumor type that is heavily dependent on glutamine for growth and survival. In this review, we highlight the preclinical evidence that supports a relationship between glutamine signaling and prostate cancer progression. We focus on the regulation of glutamine metabolism in prostate cancer through key pathways involving the androgen receptor pathway, MYC, and the PTEN/PI3K/mTOR pathway. We end with a discussion on considerations for translation of targeting glutamine metabolism as a therapeutic strategy to manage prostate cancer. Here, it is important to understand that the tumor microenvironment also plays a role in facilitating glutamine signaling and resultant prostate cancer growth. The druggability of prostate cancer glutamine metabolism is more readily achievable with our greater understanding of tumor metabolism and the advent of selective glutaminase inhibitors that have proven safe and tolerable in early-phase clinical trials.
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Affiliation(s)
- Neil Bhowmick
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Edwin Posadas
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Leigh Ellis
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen J Freedland
- Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dolores Di Vizio
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Michael R Freeman
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dan Theodorescu
- Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Division of Cancer Biology and Therapeutics, Biomedical Sciences, and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Robert Figlin
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jun Gong
- Department of Medicine, Division of Hematology and Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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20
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Miller KJ, Henry I, Maylin Z, Smith C, Arunachalam E, Pandha H, Asim M. A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer. Front Oncol 2023; 13:1129140. [PMID: 36937454 PMCID: PMC10014620 DOI: 10.3389/fonc.2023.1129140] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.
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Affiliation(s)
| | | | - Zoe Maylin
- *Correspondence: Zoe Maylin, ; Mohammad Asim,
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21
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Nätkin R, Pennanen P, Syvälä H, Bläuer M, Kesseli J, Tammela TLJ, Nykter M, Murtola TJ. Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation. PLoS One 2023; 18:e0281645. [PMID: 36809527 PMCID: PMC9942993 DOI: 10.1371/journal.pone.0281645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 01/30/2023] [Indexed: 02/23/2023] Open
Abstract
Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further.
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Affiliation(s)
- Reetta Nätkin
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University and Tays Cancer Center, Tampere, Finland
- * E-mail: (RN); (TJM)
| | - Pasi Pennanen
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Heimo Syvälä
- Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Merja Bläuer
- Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere Pancreas Laboratory and Department of Gastroenterology and Alimentary Tract Surgery, Tampere University, Tampere, Finland
| | - Juha Kesseli
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University and Tays Cancer Center, Tampere, Finland
| | - Teuvo L. J. Tammela
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Urology, Tays Cancer Center, Tampere, Finland
| | - Matti Nykter
- Faculty of Medicine and Health Technology, Prostate Cancer Research Center, Tampere University and Tays Cancer Center, Tampere, Finland
| | - Teemu J. Murtola
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Urology, Tays Cancer Center, Tampere, Finland
- * E-mail: (RN); (TJM)
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22
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Jeong SM, Bui QT, Kwak M, Lee JY, Lee PCW. Targeting Cdc20 for cancer therapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188824. [DOI: 10.1016/j.bbcan.2022.188824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/26/2022] [Accepted: 10/06/2022] [Indexed: 11/26/2022]
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Metabolic changes during prostate cancer development and progression. J Cancer Res Clin Oncol 2022; 149:2259-2270. [PMID: 36151426 PMCID: PMC10097763 DOI: 10.1007/s00432-022-04371-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/18/2022] [Indexed: 10/14/2022]
Abstract
Metabolic reprogramming has been recognised as a hallmark in solid tumours. Malignant modification of the tumour's bioenergetics provides energy for tumour growth and progression. Otto Warburg first reported these metabolic and biochemical changes in 1927. In prostate cancer (PCa) epithelial cells, the tumour metabolism also changes during development and progress. These alterations are partly driven by the androgen receptor, the key regulator in PCa development, progress, and survival. In contrast to other epithelial cells of different entities, glycolytic metabolism in prostate cells sustains physiological citrate secretion in the normal prostatic epithelium. In the early stages of PCa, citrate is utilised to power oxidative phosphorylation and fuel lipogenesis, enabling tumour growth and progression. In advanced and incurable castration-resistant PCa, a metabolic shift towards choline, amino acid, and glycolytic metabolism fueling tumour growth and progression has been described. Therefore, even if the metabolic changes are not fully understood, the altered metabolism during tumour progression may provide opportunities for novel therapeutic strategies, especially in advanced PCa stages. This review focuses on the main differences in PCa's metabolism during tumourigenesis and progression highlighting glutamine's role in PCa.
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Alanine-Serine-Cysteine Transporter 2 Inhibition Suppresses Prostate Cancer Cell Growth In Vitro. J Clin Med 2022; 11:jcm11185466. [PMID: 36143113 PMCID: PMC9501406 DOI: 10.3390/jcm11185466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/06/2022] [Accepted: 09/14/2022] [Indexed: 11/30/2022] Open
Abstract
Alanine-serine-cysteine transporter 2 (ASCT2) has been associated with increased levels of metabolism in various malignant tumors. However, its biological significance in the proliferation of prostate cancer (PCa) cells remains under investigation. We used the cBioPortal database to assess the effect of ASCT2 expression on the oncological outcomes of 108 PCa patients. To evaluate the function of ASCT2 in castration-sensitive PCa (CSPC) and castration-resistant PCa (CRPC), LNCaP cells and the ARV7-positive PCa cell line, 22Rv1, were assessed using cell proliferation assays and Western blot analyses. The ASCT2 expression level was associated with biochemical recurrence-free survival after prostatectomy in patients with a Gleason score ≥ 7. In vitro experiments indicated that the growth of LNCaP cells after combination therapy of ASCT2 siRNA and enzalutamide treatment was significantly reduced, compared to that following treatment with enzalutamide alone or ASCT2 siRNA transfection alone (p < 0.01, 0.01, respectively). After ASCT2 inhibition by siRNA transfection, the growth of 22Rv1 cells was significantly suppressed as compared with negative control siRNA via downregulation of ARV7 both in fetal bovine serum and androgen-deprivation conditions (p < 0.01, 0.01, respectively). We demonstrated that ASCT2 inhibition significantly reduced the proliferation rates of both CSPC and CRPC cells in vitro.
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Jersin RÅ, Jonassen LR, Dankel SN. The neutral amino acid transporter SLC7A10 in adipose tissue, obesity and insulin resistance. Front Cell Dev Biol 2022; 10:974338. [PMID: 36172277 PMCID: PMC9512047 DOI: 10.3389/fcell.2022.974338] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/26/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity, insulin resistance and type 2 diabetes represent major global health challenges, and a better mechanistic understanding of the altered metabolism in these conditions may give improved treatment strategies. SLC7A10, a member of the SLC7 subfamily of solute carriers, also named ASC-1 (alanine, serine, cysteine transporter-1), has recently been implicated as an important modulator of core processes in energy- and lipid metabolism, through its particularly high expression in adipocytes. In human cohorts, adipose SLC7A10 mRNA shows strong inverse correlations with insulin resistance, adipocyte size and components of the metabolic syndrome, strong heritability, and an association with type 2 diabetes risk alleles. SLC7A10 has been proposed as a marker of white as opposed to thermogenic beige and brown adipocytes, supported by increased formation of thermogenic beige adipocytes upon loss of Slc7a10 in mouse white preadipocytes. Overexpression of SLC7A10 in mature white adipocytes was found to lower the generation of reactive oxygen species (ROS) and stimulate mitochondrial respiratory capacity, while SLC7A10 inhibition had the opposite effect, indicating that SLC7A10 supports a beneficial increase in mitochondrial activity in white adipocytes. Consistent with these beneficial effects, inhibition of SLC7A10 was in mouse and human white adipocyte cultures found to increase lipid accumulation, likely explained by lowered serine uptake and glutathione production. Additionally, zebrafish with partial global Slc7a10b loss-of-function were found to have greater diet-induced body weight and larger visceral adipocytes compared to controls. However, challenging that SLC7A10 exerts metabolic benefits only in white adipocytes, suppression of SLC7A10 has been reported to decrease mitochondrial respiration and expression of thermogenic genes also in some beige and brown adipocyte cultures. Taken together, the data point to an important but complex role of SLC7A10 in metabolic regulation across different adipose tissue depots and adipocyte subtypes. Further research into SLC7A10 functions in specific adipocyte subtypes may lead to new precision therapeutics for mitigating the risk of insulin resistance and type 2 diabetes.
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Affiliation(s)
- Regine Åsen Jersin
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Laura Roxana Jonassen
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Simon Nitter Dankel
- Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
- Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
- *Correspondence: Simon Nitter Dankel,
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Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer. Cell Oncol (Dordr) 2022; 45:831-859. [PMID: 36036882 DOI: 10.1007/s13402-022-00706-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/15/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce. CONCLUSIONS AND PERSPECTIVES In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells.
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Effect of Androgen Deprivation Therapy on the Results of PET/CT with 18F-Fluciclovine in Patients with Metastatic Prostate Cancer. Tomography 2022; 8:1477-1484. [PMID: 35736868 PMCID: PMC9230844 DOI: 10.3390/tomography8030120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/16/2022] Open
Abstract
Background: 18F-fluciclovine is a positron emission tomography (PET) radiotracer approved for the detection of prostate cancer recurrence. No effect of androgen deprivation therapy (ADT) on its performance has been established. Purpose: To study the impact of concurrent ADT on disease detection with 18F-fluciclovine PET in patients with prostate cancer. Materials and Methods: Data from patients with prostate cancer who had been receiving ADT for ≥3 months at the time of undergoing an 18F-fluciclovine PET/CT at our institution were retrospectively reviewed. Seventy-three scans from 71 patients were included. The scans indicated rising prostate-specific antigen (n = 58), staging advanced disease (n = 4) or therapeutic monitoring (n = 9). Patients’ medical records provided baseline clinical data and post-scan outcomes (median follow-up 40 months). Results: Malignant lesions with increased uptake of 18F-fluciclovine were detected in 60/73 (82%) scans; 33 (45%) had lesions in the prostate/bed and 46 (63%) in extraprostatic sites. Patients received ADT for a median of 2 years (range 3 months to >10 years) pre-scan. The time on ADT did not influence detection; the detection rates were 89% for patients who had received ADT for <1 year, 63% for a treatment period of 1−<2 years, 83% for 2−4 years, 78% for >4−10 years, and 67% for a treatment period of >10 years. Conclusion: 18F-fluciclovine detected recurrent or metastatic lesions in 82% of patients with prostate cancer receiving ADT. The rates achieved in the present study are consistent with widely reported data for 18F-fluciclovine PET/CT, suggesting that withdrawal of ADT before scanning is not necessary.
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28
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Cappoli N, Jenkinson MD, Russo CD, Dickens D. LAT1, a novel pharmacological target for the treatment of glioblastoma. Biochem Pharmacol 2022; 201:115103. [PMID: 35618000 DOI: 10.1016/j.bcp.2022.115103] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/18/2022] [Accepted: 05/18/2022] [Indexed: 11/02/2022]
Abstract
The L-Type Amino Acid transporter, LAT1 (SLC7A5), has a crucial role in mediating amino acid uptake into the cells, thus modulating cell growth and proliferation as well as other intracellular functions. Different studies have reported a central role of LAT1 in glioblastoma development and progression, suggesting that the modulation of its activity could be a novel therapeutic strategy. LAT1 also has an important role in the peripheral immune system, by regulating the activation status of several immune cells through modulation of the mechanistic target of rapamycin kinase. In glioblastoma (GBM), the blood-brain barrier is disrupted, which allows the recruitment of peripheral immune cells to the tumour site. These cells, together with resident microglia, contribute to cancer growth and progression. Currently, little is known about the function of LAT1 in the reprogramming of the immune component of the tumour microenvironment in the context of GBM. In this article, we review the available data on the role of LAT1 in the regulation of GBM biology, including its potential role in the tumour microenvironment, particularly in infiltrating-peripheral immune cells and resident microglial cells. In addition, we review the available data on the main pharmacological inhibitors of LAT1, aiming to evaluate their possible role as novel therapeutics for GBM.
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Affiliation(s)
- Natalia Cappoli
- Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Michael D Jenkinson
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, United Kingdom; Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom
| | - Cinzia Dello Russo
- Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, United Kingdom.
| | - David Dickens
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, United Kingdom
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Bruno S, Ghelli Luserna di Rorà A, Napolitano R, Soverini S, Martinelli G, Simonetti G. CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies. J Exp Clin Cancer Res 2022; 41:159. [PMID: 35490245 PMCID: PMC9055704 DOI: 10.1186/s13046-022-02363-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/11/2022] [Indexed: 12/31/2022] Open
Abstract
Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration. Here, we here summarize and discuss the role of CDC20 inside and outside mitosis, starting from its network of interacting proteins. In the last years, CDC20 has also attracted more interest in the blood cancer field, being overexpressed and showing an association with prognosis both in myeloid and lymphoid malignancies. Preclinical findings showed that selective CDC20 and APC/CCDC20/APC/CCDH1 inhibitors, namely Apcin and proTAME, are effective against lymphoma and multiple myeloma cells, resulting in mitotic arrest and apoptosis and synergizing with clinically-relevant drugs. The evidence and hypothesis presented in this review provide the input for further biological and chemical studies aiming to dissect novel potential CDC20 roles and targeting strategies in hematological malignancies.
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Affiliation(s)
- Samantha Bruno
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Andrea Ghelli Luserna di Rorà
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", via Piero Maroncelli 40, 47014, Meldola, FC, Italy.
| | - Roberta Napolitano
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", via Piero Maroncelli 40, 47014, Meldola, FC, Italy
| | - Simona Soverini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology "L. e A. Seràgnoli", Bologna, Italy
| | - Giovanni Martinelli
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", via Piero Maroncelli 40, 47014, Meldola, FC, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", via Piero Maroncelli 40, 47014, Meldola, FC, Italy
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30
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Xiong T, He P, Zhou M, Zhong D, Yang T, He W, Xu Z, Chen Z, Liu YW, Dai SS. Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment. Cancer Sci 2022; 113:1955-1967. [PMID: 35363928 PMCID: PMC9207372 DOI: 10.1111/cas.15355] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Neutrophils are the first defenders of the innate system for injury and infection. They have gradually been recognized as important participants in tumor initiation and development due to their heterogeneity and plasticity. In the tumor microenvironment (TME), neutrophils can exert antitumor and protumor functions, depending on the surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms that determine how altered AAs affect neutrophils in TME are less‐explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils’ cell‐killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, flow cytometry, and western blot experiments proved that increased levels of pSTAT3/RAB10/ARF4, mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that riluzole, an FDA‐approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils’ cell‐killing effects and decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor‐released glutamate on neutrophil transformation in TME, providing new possible cancer treatments targeting altered glutamate metabolism.
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Affiliation(s)
- Tiantian Xiong
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Ping He
- Department of Cardiac Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, PR China
| | - Mi Zhou
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Dan Zhong
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Teng Yang
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Wenhui He
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Zhizhen Xu
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Zongtao Chen
- Health Management Center, Southwest Hospital, Army Medical University, Chongqing, 400038, PR China
| | - Yang-Wuyue Liu
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
| | - Shuang-Shuang Dai
- Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China
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Metabolic Phenotyping in Prostate Cancer Using Multi-Omics Approaches. Cancers (Basel) 2022; 14:cancers14030596. [PMID: 35158864 PMCID: PMC8833769 DOI: 10.3390/cancers14030596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/14/2022] [Accepted: 01/20/2022] [Indexed: 12/17/2022] Open
Abstract
Prostate cancer (PCa), one of the most frequently diagnosed cancers among men worldwide, is characterized by a diverse biological heterogeneity. It is well known that PCa cells rewire their cellular metabolism to meet the higher demands required for survival, proliferation, and invasion. In this context, a deeper understanding of metabolic reprogramming, an emerging hallmark of cancer, could provide novel opportunities for cancer diagnosis, prognosis, and treatment. In this setting, multi-omics data integration approaches, including genomics, epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics, could offer unprecedented opportunities for uncovering the molecular changes underlying metabolic rewiring in complex diseases, such as PCa. Recent studies, focused on the integrated analysis of multi-omics data derived from PCa patients, have in fact revealed new insights into specific metabolic reprogramming events and vulnerabilities that have the potential to better guide therapy and improve outcomes for patients. This review aims to provide an up-to-date summary of multi-omics studies focused on the characterization of the metabolomic phenotype of PCa, as well as an in-depth analysis of the correlation between changes identified in the multi-omics studies and the metabolic profile of PCa tumors.
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Zhao X, Sakamoto S, Maimaiti M, Anzai N, Ichikawa T. Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways. Cancers (Basel) 2022; 14:cancers14010229. [PMID: 35008399 PMCID: PMC8750950 DOI: 10.3390/cancers14010229] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/28/2021] [Accepted: 01/02/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary LAT1-4F2hc complex is an important amino acid transporter. It mainly transports specific amino acids through the cell membrane, provides nutrition for cells, and participates in a variety of metabolic pathways. LAT1 plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. However, the importance of SLCs is still not well known in the field of urological cancer. Therefore, the purpose of this review is to report the role of the LAT1-4F2hc complex in urological cancers, as well as their clinical significance and application. Moreover, the inhibitor of LAT1-4F2hc complex is a promising direction as a targeted therapy to improve the treatment and prognosis of urological cancers. Abstract Tumor cells are known for their ability to proliferate. Nutrients are essential for rapidly growing tumor cells. In particular, essential amino acids are essential for tumor cell growth. Tumor cell growth nutrition requires the regulation of membrane transport proteins. Nutritional processes require amino acid uptake across the cell membrane. Leucine, one of the essential amino acids, has recently been found to be closely associated with cancer, which activate mTOR signaling pathway. The transport of leucine into cells requires an L-type amino acid transporter protein 1, LAT1 (SLC7A5), which requires the 4F2 cell surface antigen heavy chain (4F2hc, SLC3A2) to form a heterodimeric amino acid transporter protein complex. Recent evidence identified 4F2hc as a specific downstream target of the androgen receptor splice variant 7 (AR-V7). We stressed the importance of the LAT1-4F2hc complex as a diagnostic and therapeutic target in urological cancers in this review, which covered the recent achievements in research on the involvement of the LAT1-4F2hc complex in urinary system tumors. In addition, JPH203, which is a selective LAT1 inhibitor, has shown excellent inhibitory effects on the proliferation in a variety of tumor cells. The current phase I clinical trials of JPH203 in patients with biliary tract cancer have also achieved good results, which is the future research direction for LAT1 targeted therapy drugs.
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Affiliation(s)
- Xue Zhao
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (X.Z.); (T.I.)
- Department of Urology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Shinichi Sakamoto
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (X.Z.); (T.I.)
- Correspondence: ; Tel.: +81-43-226-2134; Fax: +81-43-226-2136
| | - Maihulan Maimaiti
- Department of Tumor Pathology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan;
| | - Naohiko Anzai
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan;
| | - Tomohiko Ichikawa
- Department of Urology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; (X.Z.); (T.I.)
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Alsayed SSR, Suri A, Bailey AW, Lane S, Werry EL, Huang CC, Yu LF, Kassiou M, Sredni ST, Gunosewoyo H. Synthesis and antitumour evaluation of indole-2-carboxamides against paediatric brain cancer cells. RSC Med Chem 2021; 12:1910-1925. [PMID: 34825187 PMCID: PMC8597418 DOI: 10.1039/d1md00065a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/05/2021] [Indexed: 11/21/2022] Open
Abstract
Paediatric glioblastomas are rapidly growing, devastating brain neoplasms with an invasive phenotype. Radiotherapy and chemotherapy, which are the current therapeutic adjuvant to surgical resection, are still associated with various toxicity profiles and only marginally improve the course of the disease and life expectancy. A considerable body of evidence supports the antitumour and apoptotic effects of certain cannabinoids, such as WIN55,212-2, against a wide spectrum of cancer cells, including gliomas. In fact, we previously highlighted the potent cytotoxic activity of the cannabinoid ligand 5 against glioblastoma KNS42 cells. Taken together, in this study, we designed, synthesised, and evaluated several indoles and indole bioisosteres for their antitumour activities. Compounds 8a, 8c, 8f, 12c, and 24d demonstrated significant inhibitory activities against the viability (IC50 = 2.34-9.06 μM) and proliferation (IC50 = 2.88-9.85 μM) of paediatric glioblastoma KNS42 cells. All five compounds further retained their antitumour activities against two atypical teratoid/rhabdoid tumour (AT/RT) cell lines. When tested against a medulloblastoma DAOY cell line, only 8c, 8f, 12c, and 24d maintained their viability inhibitory activities. The viability assay against non-neoplastic human fibroblast HFF1 cells suggested that compounds 8a, 8c, 8f, and 12c act selectively towards the panel of paediatric brain tumour cells. In contrast, compound 24d and WIN55,212-2 were highly toxic toward HFF1 cells. Due to their structural resemblance to known cannabimimetics, the most potent compounds were tested in cannabinoid 1 and 2 receptor (CB1R and CB2R) functional assays. Compounds 8a, 8c, and 12c failed to activate or antagonise both CB1R and CB2R, whereas compounds 8f and 24d antagonised CB1R and CB2R, respectively. We also performed a transcriptional analysis on KNS42 cells treated with our prototype compound 8a and highlighted a set of seven genes that were significantly downregulated. The expression levels of these genes were previously shown to be positively correlated with tumour growth and progression, indicating their implication in the antitumour activity of 8a. Overall, the drug-like and selective antitumour profiles of indole-2-carboxamides 8a, 8c, 8f, and 12c substantiate the versatility of the indole scaffold in cancer drug discovery.
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Affiliation(s)
- Shahinda S R Alsayed
- Curtin Medical School, Faculty of Health Sciences, Curtin University Bentley Perth WA 6102 Australia
| | - Amreena Suri
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA
| | - Anders W Bailey
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA
| | - Samuel Lane
- School of Chemistry, The University of Sydney NSW 2006 Australia
| | - Eryn L Werry
- School of Chemistry, The University of Sydney NSW 2006 Australia
- Faculty of Medicine and Health, The University of Sydney NSW 2006 Australia
| | - Chiang-Ching Huang
- Department of Biostatistics, Zilber School of Public Health, University of Wisconsin Milwaukee WI 53205 USA
| | - Li-Fang Yu
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University 3663 North Zhongshan Road Shanghai 200062 China
| | - Michael Kassiou
- School of Chemistry, The University of Sydney NSW 2006 Australia
| | - Simone Treiger Sredni
- Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago Chicago IL 60611 USA
- Department of Surgery, Northwestern University, Feinberg School of Medicine Chicago IL 60611 USA
| | - Hendra Gunosewoyo
- Curtin Medical School, Faculty of Health Sciences, Curtin University Bentley Perth WA 6102 Australia
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Jigjidkhorloo N, Kanekura K, Matsubayashi J, Akahane D, Fujita K, Oikawa K, Kurata A, Takanashi M, Endou H, Nagao T, Gotoh A, Norov O, Kuroda M. Expression of L-type amino acid transporter 1 is a poor prognostic factor for Non-Hodgkin's lymphoma. Sci Rep 2021; 11:21638. [PMID: 34737339 PMCID: PMC8569019 DOI: 10.1038/s41598-021-00811-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 09/20/2021] [Indexed: 01/23/2023] Open
Abstract
L-type neutral amino acid transporter 1 (LAT1) is a heterodimeric membrane transport protein involved in neutral amino acid transport. LAT1 is highly expressed in various malignant solid tumors and plays an essential role in cell proliferation. However, its role in malignant lymphoma remains unknown. Here, we evaluated LAT1 expression level in tissues from 138 patients with Non-Hodgkin lymphoma (NHL). Overexpression of LAT1 was confirmed in all types of NHL and we found that there is a significant correlation between the level of LAT1 expression and lymphoma grade. The LAT1 expression was higher in aggressive types of lymphomas when compared with static types of lymphomas, suggesting that active tumor proliferation requires nutrient uptake via LAT1. The expression level of LAT1 was inversely correlated with patients’ survival span. Furthermore, pharmacological inhibition of LAT1 by a specific inhibitor JPH203 inhibits lymphoma cell growth. In conclusion, our study demonstrated that LAT1 expression can be used as a prognostic marker for patients with NHL and targeting LAT1 by JPH203 can be a novel therapeutic modality for NHL.
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Affiliation(s)
- Narangerel Jigjidkhorloo
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.,Center of Hematology and Blood & Marrow Transplantation, The First Central Hospital of Mongolia, Ulaanbaatar, 14210, Mongolia
| | - Kohsuke Kanekura
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
| | - Jun Matsubayashi
- Department of Anatomical Pathology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Daigo Akahane
- Department of Hematology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Koji Fujita
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Keiki Oikawa
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Atsushi Kurata
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Masakatsu Takanashi
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Hitoshi Endou
- J-Pharma Co., Ltd., 75-1 Ono-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0046, Japan
| | - Toshitaka Nagao
- Department of Anatomical Pathology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Akihiko Gotoh
- Department of Hematology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Oyundelger Norov
- Center of Hematology and Blood & Marrow Transplantation, The First Central Hospital of Mongolia, Ulaanbaatar, 14210, Mongolia
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
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Ahmad F, Cherukuri MK, Choyke PL. Metabolic reprogramming in prostate cancer. Br J Cancer 2021; 125:1185-1196. [PMID: 34262149 PMCID: PMC8548338 DOI: 10.1038/s41416-021-01435-5] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 04/21/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023] Open
Abstract
Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.
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Affiliation(s)
- Fahim Ahmad
- grid.48336.3a0000 0004 1936 8075Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD USA ,grid.48336.3a0000 0004 1936 8075Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD USA
| | - Murali Krishna Cherukuri
- grid.48336.3a0000 0004 1936 8075Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD USA
| | - Peter L. Choyke
- grid.48336.3a0000 0004 1936 8075Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD USA
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36
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Mello-Andrade F, Guedes APM, Pires WC, Velozo-Sá VS, Delmond KA, Mendes D, Molina MS, Matuda L, de Sousa MAM, Melo-Reis P, Gomes CC, Castro CH, Almeida MAP, Menck CFM, Batista AA, Burikhanov R, Rangnekar VM, Silveira-Lacerda E. Ru(II)/amino acid complexes inhibit the progression of breast cancer cells through multiple mechanism-induced apoptosis. J Inorg Biochem 2021; 226:111625. [PMID: 34655962 DOI: 10.1016/j.jinorgbio.2021.111625] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022]
Abstract
For some cancer subtypes, such as triple-negative breast cancer, there are no specific therapies, which leads to a poor prognosis associated with invasion and metastases. Ruthenium complexes have been developed to act in all steps of tumor growth and its progression. In this study, we investigated the effects of Ruthenium (II) complexes coupled to the amino acids methionine (RuMet) and tryptophan (RuTrp) on the induction of cell death, clonogenic survival ability, inhibition of angiogenesis, and migration of MDA-MB-231 cells (human triple-negative breast cancer). The study also demonstrated that the RuMet and RuTrp complexes induce cell cycle blockage and apoptosis of MDA-MB-231 cells, as evidenced by an increase in the number of Annexin V-positive cells, p53 phosphorylation, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. Moreover, morphological changes and loss of mitochondrial membrane potential were detected. The RuMet and RuTrp complexes induced DNA damage probably due to reactive oxygen species production related to mitochondrial membrane depolarization. Therefore, the RuMet and RuTrp complexes acted directly on breast tumor cells, leading to cell death and inhibiting their metastatic potential; this reveals the potential therapeutic action of these drugs.
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Affiliation(s)
- Francyelli Mello-Andrade
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás 74690-900, Brazil; Department of Chemistry, Federal Institute of Education, Science and Technology of Goiás, Goiânia, Goiás 74055-110, Brazil.
| | - Adriana P M Guedes
- Department of Chemistry, Federal University of São Carlos, São Carlos, SP 13565-905, Brazil
| | - Wanessa C Pires
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás 74690-900, Brazil
| | - Vivianne S Velozo-Sá
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás 74690-900, Brazil
| | - Kezia A Delmond
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás 74690-900, Brazil
| | - Davi Mendes
- Department of Microbiology, Laboratory of DNA Repair, Institute of Biomedical Sciences, University of São Paulo - USP, São Paulo, SP 05508-900, Brazil
| | - Matheus S Molina
- Department of Microbiology, Laboratory of DNA Repair, Institute of Biomedical Sciences, University of São Paulo - USP, São Paulo, SP 05508-900, Brazil
| | - Larissa Matuda
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO 74690-900, Brazil
| | | | - Paulo Melo-Reis
- Departament of Biomedicine, Pontifical Catholic University of Goiás, Goiânia, GO, Brazil
| | - Clever C Gomes
- Department of Morphology, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO 74690-900, Brazil
| | - Carlos Henrique Castro
- Department of Physiological Sciences, Institute of Biological Sciences, Federal University of Goiás - UFG, Goiânia, GO 74690-900, Brazil
| | - Márcio Aurélio P Almeida
- Coordination of Science and Technology, Federal University of Maranhão, São Luís, MA 65080-805, Brazil
| | - Carlos F M Menck
- Department of Microbiology, Laboratory of DNA Repair, Institute of Biomedical Sciences, University of São Paulo - USP, São Paulo, SP 05508-900, Brazil
| | - Alzir A Batista
- Department of Chemistry, Federal University of São Carlos, São Carlos, SP 13565-905, Brazil
| | - Ravshan Burikhanov
- Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, United States of America
| | - Vivek M Rangnekar
- Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, United States of America; L. P. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, United States of America
| | - Elisângela Silveira-Lacerda
- Department of Genetics, Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, Federal University of Goiás, Goiânia, Goiás 74690-900, Brazil.
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Stehantsev P, Stetsenko A, Nemchinova M, Aduri NG, Marrink SJ, Gati C, Guskov A. A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1. Comput Struct Biotechnol J 2021; 19:5246-5254. [PMID: 34630942 PMCID: PMC8479201 DOI: 10.1016/j.csbj.2021.09.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/14/2021] [Accepted: 09/14/2021] [Indexed: 01/30/2023] Open
Abstract
The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids' pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A number of mutations in ASCT1 (E256K, G381R, R457W) have been linked to severe neurodevelopmental disorders, however in the absence of ASCT1 structure it is hard to understand their impact on substrate transport. To ameliorate that we have determined a cryo-EM structure of human ASCT1 at 4.2 Å resolution and performed functional transport assays and molecular dynamics simulations, which revealed that given mutations lead to the diminished transport capability of ASCT1 caused by instability of transporter and impeded transport cycle.
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Affiliation(s)
- Pavlo Stehantsev
- Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
| | - Artem Stetsenko
- Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
| | - Mariia Nemchinova
- Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
| | - Nanda Gowtham Aduri
- Department of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA
| | - Siewert J. Marrink
- Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
| | - Cornelius Gati
- Department of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA
| | - Albert Guskov
- Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands
- Moscow Institute of Physics and Technology, Dolgoprudny, Russia
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38
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Kanai Y. Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther 2021; 230:107964. [PMID: 34390745 DOI: 10.1016/j.pharmthera.2021.107964] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
Cancer cells require a massive supply of nutrients, including sugars and amino acids-the upregulation of transporters for each nutrient contributes to meet the demand. Distinct from glucose transporters, amino acid transporters include ones whose expression is specific to cancer cells. For example, LAT1 (SLC7A5) displays protein expression mostly limited to the plasma membrane of cancer cells. The exceptions are the placental barrier and the blood-brain barrier, where immunohistochemical and mass spectrometric studies have shown LAT1 expression, although their levels are supposed to be lower than those in cancers. The expression of LAT1 has been reported in cancers from various tissue origins, where high LAT1 expression is related to the poor prognosis of patients. LAT1 is essential for cancer cell growth because the pharmacologic inhibition and knockdown/knockout of LAT1 suppress the proliferation of cancer cells and the growth of xenograft tumors. The inhibition of LAT1 suppresses protein synthesis by downregulating the mTORC1 signaling pathway and mobilizing the general amino acid control (GAAC) pathway in cancer cells. LAT1 is, thus, a candidate molecular target for the diagnosis and therapeutics of cancers. 18F-labeled 3-fluoro-l-α-methyl-tyrosine (FAMT) is used as a LAT1-specific PET probe for cancer detection due to the LAT1 specificity of α-methyl aromatic amino acids. FAMT accumulation is cancer-specific and avoids non-cancer lesions, including inflammation, confirming the cancer-specific expression of LAT1 in humans. Due to the cancer-specific nature, LAT1 can also be used for cancer-specific delivery of anti-tumor agents such as l-para-boronophenylalanine used for boron neutron capture therapy and α-emitting nuclide-labeled LAT1 substrates developed for nuclear medicine treatment. Based on the importance of LAT1 in cancer progression, high-affinity LAT1-specific inhibitors have been developed for anti-tumor drugs. JPH203 (KYT0353) is such a compound designed based on the structure-activity relationship of LAT1 ligands. It is one of the highest-affinity inhibitors with less affecting other transporters. It suppresses tumor growth in vivo without significant toxicity in preclinical studies at doses enough to suppress tumor growth. In the phase-I clinical trial, JPH203 appeared to provide promising activity. Because the mechanisms of action of LAT1 inhibitors are novel, with or without combination with other anti-tumor drugs, they could contribute to the treatment of cancers that do not respond to current therapy. The LAT1-specific PET probe could also be used as companion diagnostics of the LAT1-targeting therapies to select patients to whom therapeutic benefits could be expected. Recently, the cryo-EM structure of LAT1 has been solved, which would facilitate the understanding of the mechanisms of the dynamic interaction of ligands and the binding site, and further designing new compounds with higher activity.
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Affiliation(s)
- Yoshikatsu Kanai
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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39
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Martinez RS, Salji MJ, Rushworth L, Ntala C, Rodriguez Blanco G, Hedley A, Clark W, Peixoto P, Hervouet E, Renaude E, Kung SHY, Galbraith LCA, Nixon C, Lilla S, MacKay GM, Fazli L, Gaughan L, Sumpton D, Gleave ME, Zanivan S, Blomme A, Leung HY. SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer. Cancer Res 2021; 81:3664-3678. [PMID: 33985973 DOI: 10.1158/0008-5472.can-20-3694] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/15/2021] [Accepted: 05/11/2021] [Indexed: 11/16/2022]
Abstract
Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. SIGNIFICANCE: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer.
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Affiliation(s)
- Rafael S Martinez
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | - Mark J Salji
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | - Linda Rushworth
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | - Chara Ntala
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | | | - Ann Hedley
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - William Clark
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - Paul Peixoto
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
- EPIGENExp, (EPIgenetics and GENe EXPression Technical Platform), Besançon, France
| | - Eric Hervouet
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
- EPIGENExp, (EPIgenetics and GENe EXPression Technical Platform), Besançon, France
| | - Elodie Renaude
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
- EPIGENExp, (EPIgenetics and GENe EXPression Technical Platform), Besançon, France
| | - Sonia H Y Kung
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Laura C A Galbraith
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | - Colin Nixon
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - Sergio Lilla
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - Gillian M MacKay
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - Ladan Fazli
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Luke Gaughan
- Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David Sumpton
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
| | - Martin E Gleave
- Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Sara Zanivan
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
| | - Arnaud Blomme
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
| | - Hing Y Leung
- CRUK Beatson Institute, Garscube Estate, Glasgow, United Kingdom.
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom
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40
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Thompson C, Rahman MM, Singh S, Arthur S, Sierra-Bakhshi C, Russell R, Denning K, Sundaram U, Salisbury T. The Adipose Tissue-Derived Secretome (ADS) in Obesity Uniquely Induces L-Type Amino Acid Transporter 1 (LAT1) and mTOR Signaling in Estrogen-Receptor-Positive Breast Cancer Cells. Int J Mol Sci 2021; 22:6706. [PMID: 34201429 PMCID: PMC8268498 DOI: 10.3390/ijms22136706] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 01/01/2023] Open
Abstract
Obesity increases the risk of postmenopausal breast cancer (BC). This risk is mediated by obesity-induced changes in the adipose-derived secretome (ADS). The pathogenesis of BC in obesity is stimulated by mTOR hyperactivity. In obesity, leucine might support mTOR hyperactivity. Leucine uptake by BC cells is through L-Type Amino Acid Transporter 1 (LAT1). Our objective was to link obesity-ADS induction of LAT1 to the induction of mTOR signaling. Lean- and obese-ADS were obtained from lean and obese mice, respectively. Breast ADS was obtained from BC patients. Estrogen-receptor-positive BC cells were stimulated with ADS. LAT1 activity was determined by uptake of 3H-leucine. The LAT1/CD98 complex, and mTOR signaling were assayed by Western blot. The LAT1 antagonists, BCH and JPH203, were used to inhibit LAT1. Cell migration and invasion were measured by Transwell assays. The results showed obese-ADS-induced LAT1 activity by increasing transporter affinity for leucine. Consistent with this mechanism, LAT1 and CD98 expression were unchanged. Induction of mTOR by obese-ADS was inhibited by LAT1 antagonists. Breast ADS from patients with BMIs > 30 stimulated BC cell migration and invasiveness. Collectively, our findings show that obese-ADS induction of LAT1 supports mTOR hyperactivity in luminal BC cells.
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Affiliation(s)
- Chelsea Thompson
- Department of Biomedical Sciences and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA; (C.T.); (C.S.-B.)
| | - M Motiur Rahman
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA; (M.M.R.); (S.S.); (S.A.); (U.S.)
| | - Soudamani Singh
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA; (M.M.R.); (S.S.); (S.A.); (U.S.)
| | - Subha Arthur
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA; (M.M.R.); (S.S.); (S.A.); (U.S.)
| | - Cecilia Sierra-Bakhshi
- Department of Biomedical Sciences and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA; (C.T.); (C.S.-B.)
| | - Rebecca Russell
- Cabell Huntington Hospital Laboratory, Department of Pathology and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (R.R.); (K.D.)
| | - Krista Denning
- Cabell Huntington Hospital Laboratory, Department of Pathology and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA; (R.R.); (K.D.)
| | - Uma Sundaram
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA; (M.M.R.); (S.S.); (S.A.); (U.S.)
| | - Travis Salisbury
- Department of Biomedical Sciences and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA; (C.T.); (C.S.-B.)
- Department of Clinical and Translational Sciences and Appalachian Clinical and Translational Science Institute and Appalachian Center for Cellular Transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA; (M.M.R.); (S.S.); (S.A.); (U.S.)
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Pan PY, Zhu J, Rizvi A, Zhu X, Tanaka H, Dreyfus CF. Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes. J Biol Chem 2021; 297:100873. [PMID: 34126070 PMCID: PMC8258991 DOI: 10.1016/j.jbc.2021.100873] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/02/2021] [Accepted: 06/10/2021] [Indexed: 01/07/2023] Open
Abstract
Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less well understood. Missense mutations in the Synj1 gene encoding Synaptojanin1 (Synj1), a neuron-enriched lipid phosphatase, have been linked to Parkinsonism with seizures. Our previous study showed that the Synj1 haploinsufficient (Synj1+/−) mouse exhibits age-dependent autophagy impairment in multiple brain regions. Here, we used cultured astrocytes from Synj1-deficient mice to investigate its role in astrocyte autophagy. We report that Synj1 is expressed in low levels in astrocytes and represses basal autophagosome formation. We demonstrate using cellular imaging that Synj1-deficient astrocytes exhibit hyperactive autophagosome formation, represented by an increase in the size and number of GFP-microtubule-associated protein 1A/1B-light chain 3 structures. Interestingly, Synj1 deficiency is also associated with an impairment in stress-induced autophagy clearance. We show, for the first time, that the Parkinsonism-associated R839C mutation impacts autophagy in astrocytes. The impact of this mutation on the phosphatase function of Synj1 resulted in elevated basal autophagosome formation that mimics Synj1 deletion. We found that the membrane expression of the astrocyte-specific glucose transporter GluT-1 was reduced in Synj1-deficient astrocytes. Consistently, AMP-activated protein kinase activity was elevated, suggesting altered glucose sensing in Synj1-deficient astrocytes. Expressing exogenous GluT-1 in Synj1-deficient astrocytes reversed the autophagy impairment, supporting a role for Synj1 in regulating astrocyte autophagy via disrupting glucose-sensing pathways. Thus, our work suggests a novel mechanism for Synj1-related Parkinsonism involving astrocyte dysfunction.
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Affiliation(s)
- Ping-Yue Pan
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
| | - Justin Zhu
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Asma Rizvi
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Xinyu Zhu
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Hikari Tanaka
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Cheryl F Dreyfus
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
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42
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Maimaiti M, Sakamoto S, Sugiura M, Kanesaka M, Fujimoto A, Matsusaka K, Xu M, Ando K, Saito S, Wakai K, Imamura Y, Nakayama K, Kanai Y, Kaneda A, Ikehara Y, Ikeda JI, Anzai N, Ichikawa T. The heavy chain of 4F2 antigen promote prostate cancer progression via SKP-2. Sci Rep 2021; 11:11478. [PMID: 34075107 PMCID: PMC8169706 DOI: 10.1038/s41598-021-90748-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 05/05/2021] [Indexed: 11/24/2022] Open
Abstract
The 4F2 cell-surface antigen heavy chain (4F2hc) forms a heterodimeric complex with L-type amino acid transporter 1 (LAT1) and transports large neutral essential amino acids. However, in contrast to the traditional role of LAT1 in various cancers, the role of 4F2hc has largely remained unknown. The role of 4F2hc in prostate cancer was studied. Treatment of C4-2 cells with si4F2hc was found to suppress cellular growth, migratory and invasive abilities, with this effect occurring through the cell cycle, with a significant decrease in S phase and a significant increase in G0/G1 phase, suggesting cell cycle arrest. In addition, it was proven by RNA seq that the key to 4F2hc's impact on cancer is SKP2. si4F2hc upregulates the protein expression of cyclin-dependent kinase inhibitors (P21cip1, P27kip1) through the downstream target SKP2. Furthermore, the expression of 4F2hc and LAT1 in prostate cancer cells suggests the importance of 4F2hc. Multivariate analysis showed that high 4F2hc expression was an independent prognostic factor for progression-free survival (HR 11.54, p = 0.0357). High 4F2hc was related to the clinical tumour stage (p = 0.0255) and Gleason score (p = 0.0035). Collectively, 4F2hc contributed significantly to prostate cancer (PC) progression. 4F2hc may be a novel marker and therapeutic target in PC.
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Affiliation(s)
- Maihulan Maimaiti
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinichi Sakamoto
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.
| | - Masahiro Sugiura
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Manato Kanesaka
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ayumi Fujimoto
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
| | | | - Minhui Xu
- Bio-System Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Keisuke Ando
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shinpei Saito
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Ken Wakai
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
- Department of Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yusuke Imamura
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
| | - Keiichi Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yoshikatsu Kanai
- Bio-System Pharmacology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuzuru Ikehara
- Department of Tumor Pathology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Jun-Ichiro Ikeda
- Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naohiko Anzai
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomohiko Ichikawa
- Department of Urology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan
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43
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The Usefulness of STEAP Proteins in Prostate Cancer Clinical Practice. Prostate Cancer 2021. [DOI: 10.36255/exonpublications.prostatecancer.steap.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023] Open
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44
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Wang Q, Guan YF, Hancock SE, Wahi K, van Geldermalsen M, Zhang BK, Pang A, Nagarajah R, Mak B, Freidman N, Horvath LG, Turner N, Holst J. Inhibition of guanosine monophosphate synthetase (
GMPS
) blocks glutamine metabolism and prostate cancer growth. J Pathol 2021; 254:135-146. [DOI: 10.1002/path.5665] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 01/01/2023]
Affiliation(s)
- Qian Wang
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Yi Fang Guan
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Sarah E Hancock
- Mitochondrial Bioenergetics Laboratory, Department of Pharmacology School of Medical Sciences, UNSW Sydney Sydney Australia
| | - Kanu Wahi
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Michelle van Geldermalsen
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Blake K Zhang
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Angel Pang
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
| | - Rajini Nagarajah
- Origins of Cancer Program, Centenary Institute University of Sydney Camperdown Australia
- Sydney Medical School University of Sydney Sydney Australia
| | - Blossom Mak
- Chris O'Brien Lifehouse Sydney Australia
- Garvan Institute of Medical Research Sydney Australia
- University of NSW Sydney Australia
- University of Sydney Sydney Australia
| | - Natasha Freidman
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
- School of Medical Sciences, Faculty of Medicine and Health University of Sydney Sydney Australia
| | - Lisa G Horvath
- Chris O'Brien Lifehouse Sydney Australia
- Garvan Institute of Medical Research Sydney Australia
- University of NSW Sydney Australia
- University of Sydney Sydney Australia
| | - Nigel Turner
- Mitochondrial Bioenergetics Laboratory, Department of Pharmacology School of Medical Sciences, UNSW Sydney Sydney Australia
| | - Jeff Holst
- Translational Cancer Metabolism Laboratory School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney Sydney Australia
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45
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Mandigo AC, Yuan W, Xu K, Gallagher P, Pang A, Guan YF, Shafi AA, Thangavel C, Sheehan B, Bogdan D, Paschalis A, McCann JJ, Laufer TS, Gordon N, Vasilevskaya IA, Dylgjeri E, Chand SN, Schiewer MJ, Domingo-Domenech J, Den RB, Holst J, McCue PA, de Bono JS, McNair C, Knudsen KE. RB/E2F1 as a Master Regulator of Cancer Cell Metabolism in Advanced Disease. Cancer Discov 2021; 11:2334-2353. [PMID: 33879449 DOI: 10.1158/2159-8290.cd-20-1114] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/20/2021] [Accepted: 04/16/2021] [Indexed: 12/13/2022]
Abstract
Loss of the retinoblastoma (RB) tumor suppressor protein is a critical step in reprogramming biological networks that drive cancer progression, although mechanistic insight has been largely limited to the impact of RB loss on cell-cycle regulation. Here, isogenic modeling of RB loss identified disease stage-specific rewiring of E2F1 function, providing the first-in-field mapping of the E2F1 cistrome and transcriptome after RB loss across disease progression. Biochemical and functional assessment using both in vitro and in vivo models identified an unexpected, prominent role for E2F1 in regulation of redox metabolism after RB loss, driving an increase in the synthesis of the antioxidant glutathione, specific to advanced disease. These E2F1-dependent events resulted in protection from reactive oxygen species in response to therapeutic intervention. On balance, these findings reveal novel pathways through which RB loss promotes cancer progression and highlight potentially new nodes of intervention for treating RB-deficient cancers. SIGNIFICANCE: This study identifies stage-specific consequences of RB loss across cancer progression that have a direct impact on tumor response to clinically utilized therapeutics. The study herein is the first to investigate the effect of RB loss on global metabolic regulation and link RB/E2F1 to redox control in multiple advanced diseases.This article is highlighted in the In This Issue feature, p. 2113.
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Affiliation(s)
- Amy C Mandigo
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Wei Yuan
- The Institute of Cancer Research, London, United Kingdom.,The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Kexin Xu
- The University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Peter Gallagher
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Angel Pang
- School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Yi Fang Guan
- School of Medical Sciences and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Ayesha A Shafi
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Chellappagounder Thangavel
- Departments of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Beshara Sheehan
- The Institute of Cancer Research, London, United Kingdom.,The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Denisa Bogdan
- The Institute of Cancer Research, London, United Kingdom.,The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Alec Paschalis
- The Institute of Cancer Research, London, United Kingdom.,The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Jennifer J McCann
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Talya S Laufer
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Nicolas Gordon
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Irina A Vasilevskaya
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Emanuela Dylgjeri
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Saswati N Chand
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Matthew J Schiewer
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Robert B Den
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Departments of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jeff Holst
- Department of Dermatology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Peter A McCue
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Johann S de Bono
- The Institute of Cancer Research, London, United Kingdom.,The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Christopher McNair
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Karen E Knudsen
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. .,Departments of Urology, Medical Oncology and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania.,Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
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46
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Wu H, Su W, Xu H, Zhang Y, Li Y, Li X, Fan L. Applications of carbon dots on tumour theranostics. VIEW 2021. [DOI: 10.1002/viw.20200061] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Hao Wu
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Wen Su
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Huimin Xu
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Yang Zhang
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Yunchao Li
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Xiaohong Li
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
| | - Louzhen Fan
- College of Chemistry Key Laboratory of Theoretical & Computational Photochemistry, and Radiopharmaceuticals, Ministry of Education Beijing Normal University Beijing China
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47
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Kahya U, Köseer AS, Dubrovska A. Amino Acid Transporters on the Guard of Cell Genome and Epigenome. Cancers (Basel) 2021; 13:E125. [PMID: 33401748 PMCID: PMC7796306 DOI: 10.3390/cancers13010125] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Tumorigenesis is driven by metabolic reprogramming. Oncogenic mutations and epigenetic alterations that cause metabolic rewiring may also upregulate the reactive oxygen species (ROS). Precise regulation of the intracellular ROS levels is critical for tumor cell growth and survival. High ROS production leads to the damage of vital macromolecules, such as DNA, proteins, and lipids, causing genomic instability and further tumor evolution. One of the hallmarks of cancer metabolism is deregulated amino acid uptake. In fast-growing tumors, amino acids are not only the source of energy and building intermediates but also critical regulators of redox homeostasis. Amino acid uptake regulates the intracellular glutathione (GSH) levels, endoplasmic reticulum stress, unfolded protein response signaling, mTOR-mediated antioxidant defense, and epigenetic adaptations of tumor cells to oxidative stress. This review summarizes the role of amino acid transporters as the defender of tumor antioxidant system and genome integrity and discusses them as promising therapeutic targets and tumor imaging tools.
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Affiliation(s)
- Uğur Kahya
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
| | - Ayşe Sedef Köseer
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anna Dubrovska
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; (U.K.); (A.S.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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48
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Okanishi H, Ohgaki R, Okuda S, Endou H, Kanai Y. Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor. Cancer Sci 2020; 112:871-883. [PMID: 33264461 PMCID: PMC7893994 DOI: 10.1111/cas.14756] [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: 09/13/2020] [Revised: 11/28/2020] [Accepted: 11/30/2020] [Indexed: 12/13/2022] Open
Abstract
L‐type amino acid transporter 1 (LAT1) is highly expressed in various cancers and plays important roles not only in the amino acid uptake necessary for cancer growth but also in cellular signaling. Recent research studies have reported anticancer effects of LAT1 inhibitors and demonstrated their potential for cancer therapy. Here, we characterized the proteome and phosphoproteome in LAT1‐inhibited cancer cells. We used JPH203, a selective LAT1 inhibitor, and performed tandem mass tag–based quantitative proteomics and phosphoproteomics on four biliary tract cancer cell lines sensitive to JPH203. Our analysis identified hundreds to thousands of differentially expressed proteins and phosphorylated sites, demonstrating the broad influence of LAT1 inhibition. Our findings showed various functional pathways altered by LAT1 inhibition, and provided possible regulators and key kinases in LAT1‐inhibited cells. Comparison of these changes among cell lines provides insights into general pathways and regulators associated with LAT1 inhibition and particularly suggests the importance of cell cycle–related pathways and kinases. Moreover, we evaluated the anticancer effects of the combinations of JPH203 with cell cycle–related kinase inhibitors and demonstrated their potential for cancer therapy. This is the first study providing the proteome‐wide scope of both protein expression and phosphorylation signaling perturbed by LAT1 inhibition in cancer cells.
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Affiliation(s)
- Hiroki Okanishi
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Ryuichi Ohgaki
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI), Osaka University, Osaka, Japan
| | - Suguru Okuda
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | | | - Yoshikatsu Kanai
- Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiative (OTRI), Osaka University, Osaka, Japan
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49
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Interaction of the neutral amino acid transporter ASCT2 with basic amino acids. Biochem J 2020; 477:1443-1457. [PMID: 32242892 DOI: 10.1042/bcj20190859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 03/16/2020] [Accepted: 04/03/2020] [Indexed: 12/20/2022]
Abstract
Glutamine transport across cell membranes is performed by a variety of transporters, including the alanine serine cysteine transporter 2 (ASCT2). The substrate-binding site of ASCT2 was proposed to be specific for small amino acids with neutral side chains, excluding basic substrates such as lysine. A series of competitive inhibitors of ASCT2 with low µM affinity were developed previously, on the basis of the 2,4-diaminobutyric acid (DAB) scaffold with a potential positive charge in the side chain. Therefore, we tested whether basic amino acids with side chains shorter than lysine can interact with the ASCT2 binding site. Molecular docking of L-1,3-diaminopropionic acid (L-DAP) and L-DAB suggested that these compounds bind to ASCT2. Consistent with this prediction, L-DAP and L-DAB, but not ornithine, lysine or D-DAP, elicited currents when applied to ASCT2-expressing cells. The currents were carried by anions and showed the hallmark properties of ASCT2 currents induced by transported substrates. The L-DAP response could be eliminated by a competitive ASCT2 inhibitor, suggesting that binding occurs at the substrate binding site. The KM for L-DAP was weakly voltage dependent. Furthermore, the pH dependence of the L-DAP response showed that the compound can bind in several protonation states. Together, these results suggest that the ASCT2 binding site is able to recognize L-amino acids with short, basic side chains, such as the L-DAP derivative β-N-methylamino-l-Alanine (BMAA), a well-studied neurotoxin. Our results expand the substrate specificity of ASCT2 to include amino acid substrates with positively charged side chains.
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50
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Zhang J, Xu Y, Li D, Fu L, Zhang X, Bao Y, Zheng L. Review of the Correlation of LAT1 With Diseases: Mechanism and Treatment. Front Chem 2020; 8:564809. [PMID: 33195053 PMCID: PMC7606929 DOI: 10.3389/fchem.2020.564809] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/17/2020] [Indexed: 12/17/2022] Open
Abstract
LAT1 is a member of the system L transporter family. The main role of the LAT1 is to transport specific amino acids through cell membranes to provide nutrients to cells and participate in several metabolic pathways. It also contributes to the transport of hormones and some drugs, which are essential for the development and treatment of some diseases. In recent years, many studies have shown that LAT1 is related to cancer, obesity, diabetes, and other diseases. However, the specific mechanism underlying the influence of LAT1 on such conditions remains unclear. Through the increasing number of studies on LAT1, we have obtained a preliminary understanding on the function of LAT1 in diseases. These studies also provide a theoretical basis for finding treatments for LAT1-related diseases, such as cancer. This review summarizes the function and mechanism of LAT1 in different diseases and the treatment of LAT1-related diseases. It also provides support for the development of novel and reliable disease treatments.
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Affiliation(s)
- Jingshun Zhang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Ying Xu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Dandan Li
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Lulu Fu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Xueying Zhang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Yigang Bao
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Lianwen Zheng
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
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