1
|
Soto CA, Lesch ML, Becker JL, Sharipol A, Khan A, Schafer XL, Becker MW, Munger JC, Frisch BJ. Elevated Lactate in the AML Bone Marrow Microenvironment Polarizes Leukemia-Associated Macrophages via GPR81 Signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.11.13.566874. [PMID: 39185193 PMCID: PMC11343108 DOI: 10.1101/2023.11.13.566874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.
Collapse
Affiliation(s)
- Celia A Soto
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Maggie L Lesch
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
| | - Jennifer L Becker
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Azmeer Sharipol
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester School of Medicine, Rochester, NY, USA
| | - Amal Khan
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
| | - Xenia L Schafer
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Michael W Becker
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester School of Medicine, Rochester, NY, USA
| | - Joshua C Munger
- Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY, USA
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Benjamin J Frisch
- Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, NY, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Biomedical Engineering, University of Rochester School of Medicine, Rochester, NY, USA
| |
Collapse
|
2
|
McFarland KS, Hegadorn K, Betenbaugh MJ, Handlogten MW. Elevated endoplasmic reticulum pH is associated with high growth and bisAb aggregation in CHO cells. Biotechnol Bioeng 2025; 122:137-148. [PMID: 39435744 DOI: 10.1002/bit.28866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 10/23/2024]
Abstract
Chinese hamster ovary (CHO) bioprocesses, the dominant platform for therapeutic protein production, are increasingly used to produce complex multispecific proteins. Product quantity and quality are affected by intracellular conditions, but these are challenging to measure and often overlooked during process optimization studies. pH is known to impact quality attributes like protein aggregation across upstream and downstream processes, yet the effects of intracellular pH on cell culture performance are largely unknown. Recently, advances in protein biosensors have enabled investigations of intracellular environments with high spatiotemporal resolution. In this study, we integrated a fluorescent pH-sensitive biosensor into a bispecifc (bisAb)-producing cell line to investigate changes in endoplasmic reticulum pH (pHER). We then investigated how changes in lactate metabolism impacted pHER, cellular redox, and product quality in fed-batch and perfusion bioreactors. Our data show pHER rapidly increased during exponential growth to a maximum of pH 7.7, followed by a sharp drop in the stationary phase in all perfusion and fed-batch conditions. pHER decline in the stationary phase was driven by an apparent loss of cellular pH regulation that occurred despite differences in redox profiles. Finally, we found protein aggregate levels correlated most closely with pHER which provides new insights into product aggregate formation in CHO processes. An improved understanding of the intracellular changes impacting bioprocesses can ultimately help guide media optimizations, improve bioprocess control strategies, or provide new targets for cell engineering.
Collapse
Affiliation(s)
- Kevin S McFarland
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
| | - Kaitlin Hegadorn
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
| | - Michael J Betenbaugh
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
| | - Michael W Handlogten
- Cell Culture and Fermentation Sciences, BioPharmaceuticals Development R&D, AstraZeneca, Gaithersburg, USA
| |
Collapse
|
3
|
Mahadeva M, Niestępski S, Kowacz M. Modifying membrane potential synchronously controls the somite's formation periodicity and growth. Dev Biol 2025; 517:317-326. [PMID: 39521163 DOI: 10.1016/j.ydbio.2024.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/22/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Coordination between periodicity of somite formation and somite growth is crucial for regular body pattern formation during somitogenesis. Yet, the specific mechanism that links the two processes remains unclear. Using chick embryos, we demonstrate that both temporal and spatial features can be simultaneously controlled by membrane potential (Vm) of somite-forming cells. Our findings show that somites hyperpolarize as they mature, displaying step-like changes in Vm observed between specific groups of somites, reflecting the reported onset of biochemical and structural changes within them. We modify Vm by changing chemical compositions of the microenvironment of the embryo. Alteration of Vm sets a new pace of somite formation (cell migration and self-assembly) and its concurrent growth (cell proliferation) without disturbing the somite's regular aspect ratio. Our results therefore suggest that Vm has the ability to orchestrate cell proliferation, migration and self-assembly - processes that are hallmarks of embryogenesis, tumorigenesis and tissue regeneration.
Collapse
Affiliation(s)
- Manohara Mahadeva
- Department of Reproductive Immunology & Pathology, Institute of Animal Reproduction and Food Research Polish Academy of Sciences, 10-748, Olsztyn, Poland.
| | - Sebastian Niestępski
- Department of Reproductive Immunology & Pathology, Institute of Animal Reproduction and Food Research Polish Academy of Sciences, 10-748, Olsztyn, Poland.
| | - Magdalena Kowacz
- Department of Reproductive Immunology & Pathology, Institute of Animal Reproduction and Food Research Polish Academy of Sciences, 10-748, Olsztyn, Poland.
| |
Collapse
|
4
|
Cordani M, Michetti F, Zarrabi A, Zarepour A, Rumio C, Strippoli R, Marcucci F. The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities. Neoplasia 2024; 58:101076. [PMID: 39476482 PMCID: PMC11555605 DOI: 10.1016/j.neo.2024.101076] [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: 08/02/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 11/11/2024]
Abstract
Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.
Collapse
Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Federica Michetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Cristiano Rumio
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy.
| |
Collapse
|
5
|
Lei L, Dong Z, Yang F, Zhang X. Metal-Organic Nanomaterials for Tumor Metabolic Blockade and Image to Increase Tumor Therapy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:57995-58005. [PMID: 39417452 DOI: 10.1021/acsami.4c11918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
The abnormal energy metabolism level of a tumor reduces the efficiency of chemotherapy. Metal-organic nanomaterials (MONs) with high drug loading efficiency, easy processes of synthesis, and controlled drug release have shown great potential in metabolic blocking and enhancement of tumor therapy. These metal-organic nanomedicines have been reported to modulate glycolysis or oxidative phosphorylation to provide monotherapy or combined therapies in tumorous treatments. In addition, the encapsulation or coordination of fluorescent dyes into MONs endowed them with the imaging ability of tumor metabolism. Herein, this Perspective summarizes the progress of MONs as therapeutic agents or imaging probes for application during tumor metabolic blocking or imaging, providing solid inspiration for biomedical applications of effective biomaterials. In addition, the current drawbacks of MONs for further biological applications in the future were discussed, giving stimulation of innovation and development in biomedical applications of MONs.
Collapse
Affiliation(s)
- Lingling Lei
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
- School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025 P. R. China
| | - Zhe Dong
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P. R. China
| | - Fengrui Yang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Xiaobing Zhang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| |
Collapse
|
6
|
Man CH, Li C, Xu X, Zhao M. Metabolic regulation in normal and leukemic stem cells. Trends Pharmacol Sci 2024; 45:919-930. [PMID: 39306527 DOI: 10.1016/j.tips.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 10/06/2024]
Abstract
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.
Collapse
Affiliation(s)
- Cheuk-Him Man
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
| | - Changzheng Li
- Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Xi Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510030, China
| | - Meng Zhao
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Key Laboratory of Stem Cells and Tissue Engineering (Ministry of Education), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
| |
Collapse
|
7
|
Sun Z, Zhao T, Bai X, Li H, Gao J, Hao Y, Li Y, Xie Y, Hu A, Huang Q, Liu X, Zhang Y. Berberine Targets PKM2 to Activate the t-PA-Induced Fibrinolytic System and Improves Thrombosis. Pharmaceuticals (Basel) 2024; 17:1219. [PMID: 39338381 PMCID: PMC11434879 DOI: 10.3390/ph17091219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Arterial thrombosis, a condition in which thrombi form in arteries, can lead to various acute cardiovascular diseases and impact the quality of life and survival of patients. Berberine (BBR), a quaternary ammonium alkaloid, has been shown to treat these diseases. However, further exploration is needed to understand underlying mechanisms of BBR. METHODS AND RESULTS Rats were administered BBR via intramuscular injection. Then, an FeCl3-coated filter paper was applied to a carotid artery to induce thrombosis. The size of the thrombus and the blood flow velocity were evaluated by carotid ultrasound. The shape of the thrombus was observed using staining and microscopy. The expression levels of mRNA and proteins were verified. Additionally, mass spectrometry and single-cell RNA sequencing analysis were conducted. The administration of BBR resulted in a significant reduction in the thrombus area and an extension of the thrombus-clogging time. Furthermore, BBR administration effectively reversed the decreasing tissue-plasminogen activator (t-PA) expression and alterations in fibrinolysis system of model group. Additionally, the expression of PKM2 was suppressed following BBR administration, and the overexpression of PKM2 inhibited t-PA expression. CONCLUSIONS BBR ameliorates thrombosis by modulating expression of PKM2, subsequently impacting the expression of t-PA within fibrinolytic system. These preliminary findings suggest that BBR could be a potential preventive and therapeutic strategy for arterial thromboembolic diseases.
Collapse
Affiliation(s)
- Zeqi Sun
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Tong Zhao
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Xue Bai
- College of Pharmacy, Hainan University, Haikou 570228, China
| | - Huimin Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Jin Gao
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Yutong Hao
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Yiyang Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Yanli Xie
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Ange Hu
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Qiang Huang
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Xin Liu
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| | - Yong Zhang
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China
| |
Collapse
|
8
|
Jiang X, Huang K, Sun X, Li Y, Hua L, Liu F, Huang R, Du J, Zeng H. Hexamethylene amiloride synergizes with venetoclax to induce lysosome-dependent cell death in acute myeloid leukemia. iScience 2024; 27:108691. [PMID: 38205254 PMCID: PMC10776932 DOI: 10.1016/j.isci.2023.108691] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 10/15/2023] [Accepted: 12/05/2023] [Indexed: 01/12/2024] Open
Abstract
Tumors maintain an alkaline intracellular environment to enable rapid growth. The proton exporter NHE1 participates in maintenance of this pH gradient. However, whether targeting NHE1 could inhibit the growth of tumor cells remains unknown. Here, we report that the NHE1 inhibitor Hexamethylene amiloride (HA) efficiently suppresses the growth of AML cell lines. Moreover, HA combined with venetoclax synergized to efficiently inhibit the growth of AML cells. Interestingly, lysosomes are the main contributors to the synergism of HA and venetoclax in inhibiting AML cells. Most importantly, the combination of HA and venetoclax also had prominent anti-leukemia effects in both xenograft models and bone marrow samples from AML patients. In summary, our results provide evidence that the NHE1 inhibitor HA or its combination with venetoclax efficiently inhibits the growth of AML in vitro and in vivo.
Collapse
Affiliation(s)
- Xinya Jiang
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Kexiu Huang
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Xiaofan Sun
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Yue Li
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Lei Hua
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Fangshu Liu
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Rui Huang
- Department of Hematology, Zhujiang Hospital of Southern Medical University, Guangzhou, P.R. China
| | - Juan Du
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| | - Hui Zeng
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China
| |
Collapse
|
9
|
Man CH, Lam W, Dang CC, Zeng XY, Zheng LC, Chan NNM, Ng KL, Chan KC, Kwok TH, Ng TCC, Leung WY, Huen MSY, Wong CCL, So CWE, Dou Z, Goyama S, Bray MR, Mak TW, Leung AYH. Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML. Blood 2023; 142:2002-2015. [PMID: 37738460 DOI: 10.1182/blood.2023019782] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 06/29/2023] [Accepted: 07/20/2023] [Indexed: 09/24/2023] Open
Abstract
Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.
Collapse
Affiliation(s)
- Cheuk-Him Man
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Wing Lam
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chee-Chean Dang
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xiao-Yuan Zeng
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Li-Chuan Zheng
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Natalie Nok-Man Chan
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ka-Lam Ng
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Koon-Chuen Chan
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Tsz-Ho Kwok
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Timothy Chi-Chun Ng
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Wing-Yan Leung
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Michael Shing-Yan Huen
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Carmen Chak-Lui Wong
- Department of Pathology, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
| | - Chi Wai Eric So
- Department of Haematological Medicine, Leukemia and Stem Cell Biology Team, King's College London, London, UK
| | - Zhixun Dou
- Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA
| | - Susumu Goyama
- Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Mark Robert Bray
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Canada
| | - Tak Wah Mak
- Department of Pathology, The University of Hong Kong, Hong Kong SAR, China
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Canada
| | - Anskar Yu-Hung Leung
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China
| |
Collapse
|
10
|
Abstract
Cancers undergo sequential changes to proton (H+) concentration and sensing that are consequences of the disease and facilitate its further progression. The impact of protonation state on protein activity can arise from alterations to amino acids or their titration. Indeed, many cancer-initiating mutations influence pH balance, regulation or sensing in a manner that enables growth and invasion outside normal constraints as part of oncogenic transformation. These cancer-supporting effects become more prominent when tumours develop an acidic microenvironment owing to metabolic reprogramming and disordered perfusion. The ensuing intracellular and extracellular pH disturbances affect multiple aspects of tumour biology, ranging from proliferation to immune surveillance, and can even facilitate further mutagenesis. As a selection pressure, extracellular acidosis accelerates disease progression by favouring acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Although acid-base disturbances in tumours often occur alongside hypoxia and lactate accumulation, there is now ample evidence for a distinct role of H+-operated responses in key events underpinning cancer. The breadth of these actions presents therapeutic opportunities to change the trajectory of disease.
Collapse
Affiliation(s)
- Pawel Swietach
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
| | - Ebbe Boedtkjer
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Stine Falsig Pedersen
- Department of Biology, University of Copenhagen, University of Copenhagen, Faculty of Science, København, Denmark.
| |
Collapse
|
11
|
Lei L, Yang F, Meng X, Xu L, Liang P, Ma Y, Dong Z, Wang Y, Zhang XB, Song G. Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold. J Am Chem Soc 2023; 145:24386-24400. [PMID: 37883689 DOI: 10.1021/jacs.3c09473] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Chemotherapeutic resistance poses a significant challenge in cancer treatment, resulting in the reduced efficacy of standard chemotherapeutic agents. Abnormal metabolism, particularly increased anaerobic glycolysis, has been identified as a major contributing factor to chemotherapeutic resistance. To address this issue, noninvasive imaging techniques capable of visualizing tumor glycolysis are crucial. However, the currently available methods (such as PET, MRI, and fluorescence) possess limitations in terms of sensitivity, safety, dynamic imaging capability, and autofluorescence. Here, we present the de novo design of a unique afterglow molecular scaffold based on hemicyanine and rhodamine dyes, which holds promise for low-background optical imaging. In contrast to previous designs, this scaffold exhibits responsive "OFF-ON" afterglow signals through spirocyclization, thus enabling simultaneous control of photodynamic effects and luminescence efficacy. This leads to a larger dynamic range, broader detection range, higher signal enhancement ratio, and higher sensitivity. Furthermore, the integration of multiple functionalities simplifies probe design, eliminates the need for spectral overlap, and enhances reliability. Moreover, we have expanded the applications of this afterglow molecular scaffold by developing various probes for different molecular targets. Notably, we developed a water-soluble pH-responsive afterglow nanoprobe for visualizing glycolysis in living mice. This nanoprobe monitors the effects of glycolytic inhibitors or oxidative phosphorylation inhibitors on tumor glycolysis, providing a valuable tool for evaluating the tumor cell sensitivity to these inhibitors. Therefore, the new afterglow molecular scaffold presents a promising approach for understanding tumor metabolism, monitoring chemotherapeutic resistance, and guiding precision medicine in the future.
Collapse
Affiliation(s)
- Lingling Lei
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Fengrui Yang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Xin Meng
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Li Xu
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Peng Liang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Yuan Ma
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Zhe Dong
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Youjuan Wang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Xiao-Bing Zhang
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| | - Guosheng Song
- Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China
| |
Collapse
|
12
|
Zheng P, Mao Z, Luo M, Zhou L, Wang L, Liu H, Liu W, Wei S. Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma. Cancer Cell Int 2023; 23:222. [PMID: 37775731 PMCID: PMC10543265 DOI: 10.1186/s12935-023-03082-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 09/21/2023] [Indexed: 10/01/2023] Open
Abstract
According to the latest epidemiological investigation, lung adenocarcinoma (LUAD) is one of the most fatal cancer among both men and women. Despite continuous advancements in treatment approaches in recent years, the prognosis for LUAD remains relatively poor. Given the crucial role of the solute carrier (SLC) family in maintaining cellular energy metabolism stability, we conducted a comprehensive analysis of the association between SLC genes and LUAD prognosis. In the present study, we identified 71 genes among the SLC family members, of which 32 were downregulated and 39 were upregulated in LUAD samples. Based on these differentially expressed genes, a prognostic risk scoring model was established that was composed of five genes (SLC16A7, SLC16A4, SLC16A3, SLC12A8, and SLC25A15) and clinical characteristics; this model could effectively predict the survival and prognosis of patients in the cohort. Notably, SLC2A1, SLC25A29, and SLC27A4 were identified as key genes associated with survival and tumor stage. Further analysis revealed that SLC25A29 was underexpressed in LUAD tissue and regulated the phenotype of endothelial cells. Endothelial cell proliferation and migration increased and apoptosis decreased with a decrease in SLC25A29 expression. Investigation of the upstream regulatory mechanisms of SLC25A29 revealed that SLC25A29 expression gradually decreased as the lactate concentration increased. This phenomenon suggested that the expression of SLC25A29 may be related to lactylation modification. ChIP-qPCR experiments confirmed the critical regulatory role played by H3K14la and H3K18la modifications in the promoter region of SLC25A29. In conclusion, this study confirmed the role of SLC family genes in LUAD prognosis and revealed the role of SLC25A29 in regulating endothelial cell phenotypes. These study results provided important clues to further understand LUAD pathogenesis and develop appropriate therapeutic strategies.
Collapse
Affiliation(s)
- Pengdou Zheng
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Zhenyu Mao
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Miao Luo
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Lingling Wang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Huiguo Liu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Wei Liu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
| | - Shuang Wei
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
| |
Collapse
|
13
|
Tafech A, Jacquet P, Beaujean C, Fertin A, Usson Y, Stéphanou A. Characterization of the Intracellular Acidity Regulation of Brain Tumor Cells and Consequences for Therapeutic Optimization of Temozolomide. BIOLOGY 2023; 12:1221. [PMID: 37759620 PMCID: PMC10525637 DOI: 10.3390/biology12091221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/04/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023]
Abstract
A well-known feature of tumor cells is high glycolytic activity, leading to acidification of the tumor microenvironment through extensive lactate production. This acidosis promotes processes such as metastasis, aggressiveness, and invasiveness, which have been associated with a worse clinical prognosis. Moreover, the function and expression of transporters involved in regulation of intracellular pH might be altered. In this study, the capacity of tumor cells to regulate their intracellular pH when exposed to a range of pH from very acidic to basic was characterized in two glioma cell lines (F98 and U87) using a new recently published method of fluorescence imaging. Our results show that the regulation of acidity in tumors is not the same for the two investigated cell lines; U87 cells are able to reduce their intracellular acidity, whereas F98 cells do not exhibit this property. On the other hand, F98 cells show a higher level of resistance to acidity than U87 cells. Intracellular regulation of acidity appears to be highly cell-dependent, with different mechanisms activated to preserve cell integrity and function. This characterization was performed on 2D monolayer cultures and 3D spheroids. Spatial heterogeneities were exhibited in 3D, suggesting a spatially modulated regulation in this context. Based on the corpus of knowledge available in the literature, we propose plausible mechanisms to interpret our results, together with some new lines of investigation to validate our hypotheses. Our results might have implications on therapy, since the activity of temozolomide is highly pH-dependent. We show that the drug efficiency can be enhanced, depending on the cell type, by manipulating the extracellular pH. Therefore, personalized treatment involving a combination of temozolomide and pH-regulating agents can be considered.
Collapse
Affiliation(s)
| | | | | | | | | | - Angélique Stéphanou
- Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000 Grenoble, France; (A.T.); (P.J.); (C.B.); (A.F.); (Y.U.)
| |
Collapse
|
14
|
Kazyken D, Lentz SI, Wadley M, Fingar DC. Alkaline intracellular pH (pHi) increases PI3K activity to promote mTORC1 and mTORC2 signaling and function during growth factor limitation. J Biol Chem 2023; 299:105097. [PMID: 37507012 PMCID: PMC10477693 DOI: 10.1016/j.jbc.2023.105097] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
The conserved protein kinase mTOR (mechanistic target of rapamycin) responds to diverse environmental cues to control cell metabolism and promote cell growth, proliferation, and survival as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and mTORC2. Our prior work demonstrated that an alkaline intracellular pH (pHi) increases mTORC2 activity and cell survival in complete media in part by activating AMP-activated protein kinase, a kinase best known to sense energetic stress. It is important to note that an alkaline pHi represents an underappreciated hallmark of cancer cells that promotes their oncogenic behaviors. In addition, mechanisms that control mTORC1 and mTORC2 signaling and function remain incompletely defined, particularly in response to stress conditions. Here, we demonstrate that an alkaline pHi increases phosphatidylinositide 3-kinase (PI3K) activity to promote mTORC1 and mTORC2 signaling in the absence of serum growth factors. Alkaline pHi increases mTORC1 activity through PI3K-Akt signaling, which mediates inhibitory phosphorylation of the upstream proteins tuberous sclerosis complex 2 and proline-rich Akt substrate of 40 kDa and dissociates tuberous sclerosis complex from lysosomal membranes, thus enabling Rheb-mediated activation of mTORC1. Thus, alkaline pHi mimics growth factor-PI3K signaling. Functionally, we also demonstrate that an alkaline pHi increases cap-dependent protein synthesis through inhibitory phosphorylation of eIF4E binding protein 1 and suppresses apoptosis in a PI3K- and mTOR-dependent manner. We speculate that an alkaline pHi promotes a low basal level of cell metabolism (e.g., protein synthesis) that enables cancer cells within growing tumors to proliferate and survive despite limiting growth factors and nutrients, in part through elevated PI3K-mTORC1 and/or PI3K-mTORC2 signaling.
Collapse
Affiliation(s)
- Dubek Kazyken
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
| | - Stephen I Lentz
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Maxwell Wadley
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Diane C Fingar
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
| |
Collapse
|
15
|
Dausinas Ni P, Hartman M, Slack J, Basile C, Liu S, Wan J, O'Leary HA. Novel differential calcium regulation of hematopoietic stem and progenitor cells under physiological low oxygen conditions. J Cell Physiol 2023. [PMID: 37051890 DOI: 10.1002/jcp.30942] [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: 03/14/2022] [Revised: 11/28/2022] [Accepted: 12/23/2022] [Indexed: 04/14/2023]
Abstract
Low oxygen bone marrow (BM) niches (~1%-4% low O2 ) provide critical signals for hematopoietic stem/progenitor cells (HSC/HSPCs). Our presented data are the first to investigate live, sorted HSC/HSPCs in their native low O2 conditions. Transcriptional and proteomic analysis uncovered differential Ca2+ regulation that correlated with overlapping phenotypic populations consisting of robust increases of cytosolic and mitochondrial Ca2+ , ABC transporter (ABCG2) expression and sodium/hydrogen exchanger (NHE1) expression in live, HSC/HSPCs remaining in constant low O2. We identified a novel Ca2+ high population in HSPCs predominantly detected in low O2 that displayed enhanced frequency of phenotypic LSK/LSKCD150 in low O2 replating assays compared to Ca2+ low populations. Inhibition of the Ca2+ regulator NHE1 (Cariporide) resulted in attenuation of both the low O2 induced Ca2+ high population and subsequent enhanced maintenance of phenotypic LSK and LSKCD150 during low O2 replating. These data reveal multiple levels of differential Ca2+ regulation in low O2 resulting in phenotypic, signaling, and functional consequences in HSC/HSPCs.
Collapse
Affiliation(s)
- Paige Dausinas Ni
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Melissa Hartman
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jacob Slack
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Christopher Basile
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jun Wan
- Department of Medical and Molecular Genetics, Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Heather A O'Leary
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| |
Collapse
|
16
|
Zeng X, Wang YP, Man CH. Metabolism in Hematopoiesis and Its Malignancy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:45-64. [PMID: 38228958 DOI: 10.1007/978-981-99-7471-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells that can self-renew and generate all blood cells of different lineages. The system is under tight control in order to maintain a precise equilibrium of the HSC pool and the effective production of mature blood cells to support various biological activities. Cell metabolism can regulate different molecular activities, such as epigenetic modification and cell cycle regulation, and subsequently affects the function and maintenance of HSC. Upon malignant transformation, oncogenic drivers in malignant hematopoietic cells can remodel the metabolic pathways for supporting the oncogenic growth. The dysregulation of metabolism results in oncogene addiction, implying the development of malignancy-specific metabolism-targeted therapy. In this chapter, we will discuss the significance of different metabolic pathways in hematopoiesis, specifically, the distinctive metabolic dependency in hematopoietic malignancies and potential metabolic therapy.
Collapse
Affiliation(s)
- Xiaoyuan Zeng
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yi-Ping Wang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cheuk-Him Man
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| |
Collapse
|
17
|
Cappellesso F, Orban MP, Shirgaonkar N, Berardi E, Serneels J, Neveu MA, Di Molfetta D, Piccapane F, Caroppo R, Debellis L, Ostyn T, Joudiou N, Mignion L, Richiardone E, Jordan BF, Gallez B, Corbet C, Roskams T, DasGupta R, Tejpar S, Di Matteo M, Taverna D, Reshkin SJ, Topal B, Virga F, Mazzone M. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. NATURE CANCER 2022; 3:1464-1483. [PMID: 36522548 PMCID: PMC9767871 DOI: 10.1038/s43018-022-00470-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 10/21/2022] [Indexed: 12/23/2022]
Abstract
Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.
Collapse
Affiliation(s)
- Federica Cappellesso
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Marie-Pauline Orban
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Niranjan Shirgaonkar
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Emanuele Berardi
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Jens Serneels
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Marie-Aline Neveu
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Daria Di Molfetta
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
| | - Francesca Piccapane
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
| | - Rosa Caroppo
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
| | - Lucantonio Debellis
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
| | - Tessa Ostyn
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Nicolas Joudiou
- Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Lionel Mignion
- Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Elena Richiardone
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérmentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Bénédicte F Jordan
- Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Bernard Gallez
- Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium
| | - Cyril Corbet
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérmentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Tania Roskams
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Ramanuj DasGupta
- Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Sabine Tejpar
- Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Mario Di Matteo
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Daniela Taverna
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Stephan J Reshkin
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy
| | - Baki Topal
- Department of Abdominal Surgery, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Federico Virga
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
- Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium.
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
| |
Collapse
|
18
|
Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma. Cells 2022; 11:cells11213467. [DOI: 10.3390/cells11213467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.
Collapse
|
19
|
Bogdanov A, Bogdanov A, Chubenko V, Volkov N, Moiseenko F, Moiseyenko V. Tumor acidity: From hallmark of cancer to target of treatment. Front Oncol 2022; 12:979154. [PMID: 36106097 PMCID: PMC9467452 DOI: 10.3389/fonc.2022.979154] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/08/2022] [Indexed: 12/16/2022] Open
Abstract
Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to "ion trapping". Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.
Collapse
Affiliation(s)
- Alexey Bogdanov
- Saint Petersburg Clinical Research and Practical Center of Specialized Types of Medical Care (Oncological), Saint Petersburg, Russia
| | | | | | | | | | | |
Collapse
|
20
|
Li B, Liu Y, Sun S. Pump proton inhibitors display anti-tumour potential in glioma. Cell Prolif 2022:e13321. [PMID: 35961680 DOI: 10.1111/cpr.13321] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/28/2022] [Accepted: 07/14/2022] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVES Glioma is one of the most aggressive brain tumours with poor overall survival despite advanced technology in surgical resection, chemotherapy and radiation. Progression and recurrence are the hinge causes of low survival. Our aim is to explain the concrete mechanism in the proliferation and progression of tumours based on tumour microenvironment (TME). The main purpose is to illustrate the mechanism of proton pump inhibitors (PPIs) in affecting acidity, hypoxia, oxidative stress, inflammatory response and autophagy based on the TME to induce apoptosis and enhance the sensitivity of chemoradiotherapy. FINDINGS TME is the main medium for tumour growth and progression. Acidity, hypoxia, inflammatory response, autophagy, angiogenesis and so on are the main causes of tumour progress. PPIs, as a common clinical drug to inhibit gastric acid secretion, have the advantages of fast onset, long action time and small adverse reactions. Nowadays, several kinds of literature highlight the potential of PPIs in inhibiting tumour progression. However, long-term use of PPIs alone also has obvious side effects. Therefore, till now, how to apply PPIs to promote the effect of radio-chemotherapy and find the concrete dose and concentration of combined use are novel challenges. CONCLUSIONS PPIs display the potential in enhancing the sensitivity of chemoradiotherapy to defend against glioma based on TME. In the clinic, it is also necessary to explore specific concentrations and dosages in synthetic applications.
Collapse
Affiliation(s)
- Bihan Li
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin 130021, China
| | - Ying Liu
- Department of Toxicology, School of Public Health, Jilin University, Changchun, Jilin 130021, China
| | - Shilong Sun
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|
21
|
Gong YY, Shao H, Li Y, Brafford P, Stine ZE, Sun J, Felsher DW, Orange JS, Albelda SM, Dang CV. Na +/H +-exchanger 1 enhances antitumor activity of engineered NK-92 natural killer cells. CANCER RESEARCH COMMUNICATIONS 2022; 2:842-856. [PMID: 36380966 PMCID: PMC9648415 DOI: 10.1158/2767-9764.crc-22-0270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 06/16/2023]
Abstract
Adoptive cell transfer (ACT) immunotherapy has remarkable efficacy against some hematological malignancies. However, its efficacy in solid tumors is limited by the adverse tumor microenvironment (TME) conditions, most notably that acidity inhibits T and natural killer (NK) cell mTOR complex 1 (mTORC1) activity and impairs cytotoxicity. In several reported studies, systemic buffering of tumor acidity enhanced the efficacy of immune checkpoint inhibitors. Paradoxically, we found in a c-Myc-driven hepatocellular carcinoma model that systemic buffering increased tumor mTORC1 activity, negating inhibition of tumor growth by anti-PD1 treatment. Therefore, in this proof-of-concept study, we tested the metabolic engineering of immune effector cells to mitigate the inhibitory effect of tumor acidity while avoiding side effects associated with systemic buffering. We first overexpressed an activated RHEB in the human NK cell line NK-92, thereby rescuing acid-blunted mTORC1 activity and enhancing cytolytic activity. Then, to directly mitigate the effect of acidity, we ectopically expressed acid extruder proteins. Whereas ectopic expression of carbonic anhydrase IX (CA9) moderately increased mTORC1 activity, it did not enhance effector function. In contrast, overexpressing a constitutively active Na+/H+-exchanger 1 (NHE1; SLC9A1) in NK-92 did not elevate mTORC1 but enhanced degranulation, target engagement, in vitro cytotoxicity, and in vivo antitumor activity. Our findings suggest the feasibility of overcoming the inhibitory effect of the TME by metabolically engineering immune effector cells, which can enhance ACT for better efficacy against solid tumors.
Collapse
Affiliation(s)
- Yao-Yu Gong
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Yu Li
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | | | | | - Jing Sun
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dean W. Felsher
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Jordan S. Orange
- Department of Pediatrics, Columbia University Medical Center, New York, New York
| | - Steven M. Albelda
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Chi V. Dang
- The Wistar Institute, Philadelphia, Pennsylvania
- Ludwig Institute for Cancer Research, New York, New York
| |
Collapse
|
22
|
Liu Y, Cui DX, Pan Y, Yu SH, Zheng LW, Wan M. Metabolic-epigenetic nexus in regulation of stem cell fate. World J Stem Cells 2022; 14:490-502. [PMID: 36157525 PMCID: PMC9350619 DOI: 10.4252/wjsc.v14.i7.490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/31/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Stem cell fate determination is one of the central questions in stem cell biology, and although its regulation has been studied at genomic and proteomic levels, a variety of biological activities in cells occur at the metabolic level. Metabolomics studies have established the metabolome during stem cell differentiation and have revealed the role of metabolites in stem cell fate determination. While metabolism is considered to play a biological regulatory role as an energy source, recent studies have suggested the nexus between metabolism and epigenetics because several metabolites function as cofactors and substrates in epigenetic mechanisms, including histone modification, DNA methylation, and microRNAs. Additionally, the epigenetic modification is sensitive to the dynamic metabolites and consequently leads to changes in transcription. The nexus between metabolism and epigenetics proposes a novel stem cell-based therapeutic strategy through manipulating metabolites. In the present review, we summarize the possible nexus between metabolic and epigenetic regulation in stem cell fate determination, and discuss the potential preventive and therapeutic strategies via targeting metabolites.
Collapse
Affiliation(s)
- Yi Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Di-Xin Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yue Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Han Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Wei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mian Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
23
|
Dong W, Rawat ES, Stephanopoulos G, Abu-Remaileh M. Isotope tracing in health and disease. Curr Opin Biotechnol 2022; 76:102739. [PMID: 35738210 PMCID: PMC9555185 DOI: 10.1016/j.copbio.2022.102739] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/16/2022] [Accepted: 04/27/2022] [Indexed: 11/16/2022]
Abstract
Biochemical characterization of metabolism provides molecular insights for understanding biology in health and disease. Over the past decades, metabolic perturbations have been implicated in cancer, neurodegeneration, and diabetes, among others. Isotope tracing is a technique that allows tracking of labeled atoms within metabolites through biochemical reactions. This technique has become an integral component of the contemporary metabolic research. Isotope tracing measures substrate contribution to downstream metabolites and indicates its utilization in cellular metabolic networks. In addition, isotopic labeling data are necessary for quantitative metabolic flux analysis. Here, we review recent work utilizing metabolic tracing to study health and disease, and highlight its application to interrogate subcellular, intercellular, and in vivo metabolism. We further discuss the current challenges and opportunities to expand the utility of isotope tracing to new research areas.
Collapse
Affiliation(s)
- Wentao Dong
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Eshaan S Rawat
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Gregory Stephanopoulos
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| | - Monther Abu-Remaileh
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
| |
Collapse
|
24
|
Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication. Leukemia 2022; 36:1990-2001. [PMID: 35624145 PMCID: PMC9343251 DOI: 10.1038/s41375-022-01606-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 11/21/2022]
Abstract
Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRASG12D, and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.
Collapse
|