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Huang B, Shen W, Jia Y, Qin L, Wang H, Sun Q, Xiao Z, Zhang R, Wang H. LDHAα, a lactate dehydrogenase A isoform, promotes glycolysis and tumor progression. FEBS J 2025; 292:2223-2236. [PMID: 39828959 DOI: 10.1111/febs.17374] [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: 05/24/2024] [Revised: 09/25/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025]
Abstract
Lactate dehydrogenase A (LDHA) is upregulated in multiple cancer types and contributes to the Warburg effect. Several studies have found that many tumor-related genes have subtypes and play important roles in promoting cancer development. Here, we identified a novel LDHA transcript, which produced a new protein 3 kDa larger than LDHA, which we named LDHAα. We found that multiple cancer cell lines express LDHAα, and ectopic expression of LDHAα led to a higher proliferation and migration rate in vitro. Ectopic expression of LDHAα could also promote tumor cell growth in vivo. Conversely, deletion of LDHAα by CRISPR-sgRNA significantly inhibited the growth of tumor cells. LDHAα was found to be mainly located in the cytoplasm, and overexpression or deletion of LDHAα could significantly affect the glucose uptake and lactate production of tumor cells. Further investigation showed that c-MYC and FOXM1 could markedly modulate the expression of both LDHA and LDHAα, especially c-MYC. We found that a small molecular compound targeting LDHA could also inhibit the enzyme activity of LDHAα. LDHAα, LDHA and c-MYC expression was significantly higher in human acute lymphocytic leukemia and colorectal cancer tissue specimens compared to normal controls. In conclusion, our study identified LDHAα as a subtype of LDHA and highlighted its critical role in tumor metabolism, providing a potential new therapeutic target for tumor diagnosis and treatment.
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Affiliation(s)
- Bingqing Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Wencui Shen
- Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Hospital & Eye Institute, NanKai University, Tianjin, China
| | - Yujiao Jia
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Li Qin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Haoxu Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qi Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Rongxin Zhang
- Laboratory of Immunology and Inflammation, Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Huijun Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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Jafary F, Moradi A, Ganjalikhany MR, Hassanpour Dehnavi A, Seifati SM, Khodarahmi A, Hemati M. Investigation of the inhibitory peptide effect as novel strategy in cancer treatment: Targeting the tetramerization of lactate dehydrogenase A. Int J Biol Macromol 2025; 306:140878. [PMID: 39988151 DOI: 10.1016/j.ijbiomac.2025.140878] [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: 08/07/2024] [Revised: 02/02/2025] [Accepted: 02/08/2025] [Indexed: 02/25/2025]
Abstract
The Warburg effect is detected in numerous types of solid tumors and is characterized by the enhancement of glucose consumption and an increase in the rate of glycolysis in cancer cells. Lactate dehydrogenase A (LDHA) plays a critical role in the Warburg effect and to date, a number of LDHA inhibitors have been identified that act as competitive inhibitors of both the substrate pyruvate and the coenzyme NADH. In our previous study, a set of novel peptides were designed using in silico structure-based method with the aim of inhibiting the activity of LDHA by disrupting the interaction between its enzyme subunits. In the present study employed in vitro and in vivo techniques, to explore the influence of these peptides on the induction of cytotoxicity effect on cancer cell lines. Our findings revealed that the designed peptide effectively inhibits LDHA, leading to the induction of apoptosis and G2/M cell cycle arrest. Finally, we also analyzed the impact of the designed peptide on Balb/c mice, confirming the results of in silico and in vitro studies. Ultimately, the designed peptide had the ability to induce apoptosis in cancer cells by LDHA inhibition.
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Affiliation(s)
- Farzaneh Jafary
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Clinical Research Development Center, Najafabad Branch, Islamic Azad University, Najafabad, Iran
| | - Ali Moradi
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
| | - Mohamad Reza Ganjalikhany
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Azam Hassanpour Dehnavi
- Department of Anatomical Sciences, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Mohammad Seifati
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ameneh Khodarahmi
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
| | - Mahdie Hemati
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Medical Nanotechnology and Tissue Engineering Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Chen X, Liu HY, Zhou WB, Zhang LL, Huang J, Bao DW. Hypoxia-inducible factor 1-alpha and lactate dehydrogenase-A axis in metabolic changes and aggression in esophageal squamous-cell carcinoma. World J Gastrointest Oncol 2025; 17:103450. [PMID: 40092940 PMCID: PMC11866222 DOI: 10.4251/wjgo.v17.i3.103450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Esophageal squamous-cell carcinoma (ESCC) is a highly aggressive cancer, predominantly affecting populations in Eastern Asia and parts of Africa. Its pathogenesis is influenced by both genetic and environmental factors. Despite recent therapeutic advances, survival rates remain dismal, underscoring an urgent need for novel therapeutic targets. AIM To investigate the role of hypoxia-inducible factor 1-alpha (HIF1A) in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A (LDHA), which is crucial for the glycolytic pathway in hypoxic tumor environments. METHODS Utilizing transcriptomic data from multiple public databases, we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses. The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines. RESULTS Our findings reveal a significant upregulation of HIF1A in ESCC tissues, associated with poor prognosis. HIF1A directly regulates LDHA, enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness. Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis. CONCLUSION The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target, underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.
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Affiliation(s)
- Xia Chen
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Hai-Yan Liu
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Wu-Bi Zhou
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Li-Li Zhang
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Jian Huang
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Da-Wei Bao
- Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
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Lin PI, Lee YC, Chen IH, Chung HH. Pharmacological Modulation of Mutant TP53 with Oncotargets Against Esophageal Cancer and Therapy Resistance. Biomedicines 2025; 13:450. [PMID: 40002862 PMCID: PMC11852872 DOI: 10.3390/biomedicines13020450] [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: 01/02/2025] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/27/2025] Open
Abstract
The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is still required. This review briefly describes and summarizes some insightful oncotargets involved in the metabolic modulation of EC, including (1) cancer stem cells (CSCs) for EC progression, poor prognosis, tumor recurrence, and therapy resistance; (2) retinoic acid receptors (RARs) for esophageal carcinogenesis and regeneration; (3) phosphofructokinase (PFK) for EC-reprogrammed glycolysis; (4) lactate dehydrogenase (LDH) as an EC peripheral blood biomarker; and (5) hypoxia-inducible factor-1 alpha (HIF-1α) for the tumor microenvironment under hypoxic conditions. Moreover, the aforementioned oncotargets can be modulated by mutant TP53 and have their own features in the carcinogenesis, differentiation, proliferation, and metastasis of EC. Thus, the clarification of pharmacological mechanisms regarding the interaction between mutant TP53 and the abovementioned oncotargets could provide precise and perspective opinions for minimizing prediction errors, reducing therapy resistance, and developing novel drugs against EC.
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Affiliation(s)
- Pei-I Lin
- Department of Nursing, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 833401, Taiwan;
| | - Yu-Cheng Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei City 110301, Taiwan;
| | - I-Hung Chen
- Division of Urology, Department of Surgery, National Cheng Kung University Hospital Douliu Branch, Yunlin County 640003, Taiwan;
| | - Hsien-Hui Chung
- Department of Pharmacy & Clinical Trial Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung City 813414, Taiwan
- St. Edmund Hall, University of Oxford, Oxford OX1 4AR, UK
- Preventive Medicine Program, Center for General Education, Chung Yuan Christian University, Taoyuan City 320314, Taiwan
- Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung County 907101, Taiwan
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Cheon SY, Kim YE, Yang ES, Lim YJ, Bae CH, Jin JS, Park W, Kim BS, Kim C, Cho H, Kim S, Lee SH, Ha KT. Synthesis of 1-Hydroxy(and 1-Alkoxy, 1-Acyloxy)-1H-indoles and evaluations of their suppressive activities against tumor growth through inhibiting lactate dehydrogenase A. Eur J Med Chem 2025; 283:117104. [PMID: 39642694 DOI: 10.1016/j.ejmech.2024.117104] [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: 10/07/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
Inhibition of lactate dehydrogenase (LDH) has emerged as a promising cancer therapy strategy due to its essential role in the metabolic transformation of cancer cells. In this study, 53 derivatives of 1-hydroxy(and 1-alkoxy, 1-acyloxy)indoles were designed, synthesized, and biologically evaluated. Several multi-substituted 1-hydroxy(and 1-alkoxy, 1-acyloxy)indole compounds exhibited inhibitory activity against the LDH-A isoform (LDHA). We confirmed that the C(3)-substituent provided additional significant hydrogen bonding and hydrophobic interactions, which enhanced the LDHA inhibitory activity with high selectivity. Our results revealed that methyl 4-bromo-3-[(n-hexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (1g), selectively inhibited LDHA (IC50 = 25 ± 1.12 nM) without affecting the LDH-B isoform (LDHB). The compound exhibited potent cytotoxic activity in several cancer cell lines, including DLD-1 colorectal cancer cells (GI50 = 27 ± 1.2 μM). Compound 1g significantly inhibited cancer cell growth by activating apoptotic pathways in a xenograft cancer model, without causing weight loss or liver and kidney damage. Therefore, compound 1g may serve as a highly specific and promising candidate for the development of LDHA inhibitors for cancer therapy.
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Affiliation(s)
- Se-Yun Cheon
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Ye Eun Kim
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea
| | - Eun-Sun Yang
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Yoo Jin Lim
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea
| | - Chang-Hwan Bae
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Jung-Sook Jin
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Wonyoung Park
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Bo-Sung Kim
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Chorong Kim
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea
| | - Hyunsung Cho
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea
| | - Seungtae Kim
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea
| | - Sang Hyup Lee
- College of Pharmacy and Innovative Drug Center, Duksung Women's University, Seoul, 01369, Republic of Korea.
| | - Ki-Tae Ha
- Korean Medical Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea; Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 50612, Republic of Korea.
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Dong XM, Chen L, Xu YX, Wu P, Xie T, Liu ZQ. Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies. Cancer Gene Ther 2025; 32:165-183. [PMID: 39794467 DOI: 10.1038/s41417-024-00858-5] [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: 10/18/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 01/13/2025]
Abstract
Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.
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Affiliation(s)
- Xue-Man Dong
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Lin Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Yu-Xin Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Pu Wu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.
| | - Zhao-Qian Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
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Cong Y, Cui X, Shi Y, Pan X, Huang K, Geng Z, Xu P, Ge L, Zhu J, Xu J, Jia X. Tripartite-motif 3 represses ovarian cancer progression by downregulating lactate dehydrogenase A and inhibiting AKT signaling. Mol Cell Biochem 2024; 479:3405-3424. [PMID: 38367118 DOI: 10.1007/s11010-023-04920-y] [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: 07/16/2023] [Accepted: 12/19/2023] [Indexed: 02/19/2024]
Abstract
The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.
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Affiliation(s)
- Yu Cong
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Xin Cui
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Yaqian Shi
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Xinxing Pan
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Ke Huang
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Zhe Geng
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Pengfei Xu
- Nanjing Maternal and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), Nanjing, 210004, Jiangsu, China
| | - Lili Ge
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China
| | - Jin Zhu
- Department of Epidemiology and Microbiology, Huadong Medical Institute of Biotechniques, Nanjing, 210002, Jiangsu, China
| | - Juan Xu
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China.
| | - Xuemei Jia
- Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China.
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Ding P, Yang K, Wang H, Kuang L, Gao L, Luo J, Tuo X. Exploring the therapeutic potential of rutin through investigating its inhibitory mechanism on lactate dehydrogenase: Multi-spectral methods and computer simulation. Bioorg Chem 2024; 149:107503. [PMID: 38823312 DOI: 10.1016/j.bioorg.2024.107503] [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: 04/14/2024] [Revised: 05/20/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
Lactate dehydrogenase (LDH), a crucial enzyme in anaerobic glycolysis, plays a pivotal role in the energy metabolism of tumor cells, positioning it as a promising target for tumor treatment. Rutin, a plant-based flavonoid, offers benefits like antioxidant, antiapoptotic, and antineoplastic effects. This study employed diverse experiments to investigate the inhibitory mechanism of rutin on LDH through a binding perspective. The outcomes revealed that rutin underwent spontaneous binding within the coenzyme binding site of LDH, leading to the formation of a stable binary complex driven by hydrophobic forces, with hydrogen bonds also contributing significantly to sustaining the stability of the LDH-rutin complex. The binding constant (Ka) for the LDH-rutin system was 2.692 ± 0.015 × 104 M-1 at 298 K. Furthermore, rutin induced the alterations in the secondary structure conformation of LDH, characterized by a decrease in α-helix and an increase in antiparallel and parallel β-sheet, and β-turn. Rutin augmented the stability of coenzyme binding to LDH, which could potentially hinder the conversion process among coenzymes. Specifically, Arg98 in the active site loop of LDH provided essential binding energy contribution in the binding process. These outcomes might explain the dose-dependent inhibition of the catalytic activity of LDH by rutin. Interestingly, both the food additives ascorbic acid and tetrahydrocurcumin could reduce the binding stability of LDH and rutin. Meanwhile, these food additives did not produce positive synergism or antagonism on the rutin binding to LDH. Overall, this research could offer a unique insight into the therapeutic potential and medicinal worth of rutin.
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Affiliation(s)
- Pei Ding
- School of Pharmacy, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Kaiyu Yang
- School of Pharmacy, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Huixiao Wang
- School of Chemistry and Chemical Engineering, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Lin Kuang
- School of Pharmacy, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Linna Gao
- School of Chemistry and Chemical Engineering, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Jiaqing Luo
- School of Chemistry and Chemical Engineering, Nanchang University, Nanchang 330031, Jiangxi, China
| | - Xun Tuo
- School of Chemistry and Chemical Engineering, Nanchang University, Nanchang 330031, Jiangxi, China.
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9
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Ajam-Hosseini M, Heydari R, Rasouli M, Akhoondi F, Asadi Hanjani N, Bekeschus S, Doroudian M. Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy. Biochem Pharmacol 2024; 222:116098. [PMID: 38431231 DOI: 10.1016/j.bcp.2024.116098] [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: 11/24/2023] [Revised: 02/19/2024] [Accepted: 02/26/2024] [Indexed: 03/05/2024]
Abstract
Cancer remains a formidable challenge, continually revealing its intricate nature and demanding novel treatment approaches. Within this intricate landscape, the tumor microenvironment and its dynamic components have gained prominence, particularly macrophages that can adopt diverse polarization states, exerting a profound influence on cancer progression. Recent revelations have spotlighted lactic acid as a pivotal player in this complex interplay. This review systematically explores lactic acid's multifaceted role in macrophage polarization, focusing on its implications in carcinogenesis. We commence by cultivating a comprehensive understanding of the tumor microenvironment and the pivotal roles played by macrophages. The dynamic landscape of macrophage polarization, typified by M1 and M2 phenotypes, is dissected to reveal its substantial impact on tumor progression. Lactic acid, a metabolic byproduct, emerges as a key protagonist, and we meticulously unravel the mechanisms underpinning its generation within cancer cells, shedding light on its intimate association with glycolysis and its transformative effects on the tumor microenvironment. Furthermore, we decipher the intricate molecular framework that underlies lactic acid's pivotal role in facilitating macrophage polarization. Our review underscores lactic acid's dual role in carcinogenesis, orchestrating tumor growth and immune modulation within the tumor microenvironment, thereby profoundly influencing the balance between pro-tumor and anti-tumor immune responses. This duality highlights the therapeutic potential of selectively manipulating lactic acid metabolism for cancer treatment. Exploring strategies to inhibit lactic acid production by tumor cells, novel approaches to impede lactic acid transport in the tumor microenvironment, and the burgeoning field of immunotherapeutic cancer therapies utilizing lactic acid-induced macrophage polarization form the core of our investigation.
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Affiliation(s)
- Mobarakeh Ajam-Hosseini
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Romina Heydari
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Milad Rasouli
- Department of Physics, Kharazmi University, Tehran, Iran; Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Fatemeh Akhoondi
- Department of Molecular Biology of the Cell, Faculty of Bioscience, University of Milan, Milan, Italy
| | - Niloofar Asadi Hanjani
- Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran; Student Research Committee, Pasteur Institute of Iran, Tehran, Iran
| | - Sander Bekeschus
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str 2, 17489 Greifswald, Germany; Clinic and Policlinic for Dermatology and Venerology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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10
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Jia C, Wu Y, Gao F, Liu W, Li N, Chen Y, Sun L, Wang S, Yu C, Bao Y, Song Z. The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions. Free Radic Biol Med 2024; 214:2-18. [PMID: 38307156 DOI: 10.1016/j.freeradbiomed.2024.01.043] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/16/2024] [Accepted: 01/24/2024] [Indexed: 02/04/2024]
Abstract
Due to insufficient and defective vascularization, the tumor microenvironment is often nutrient-depleted. LDHA has been demonstrated to play a tumor-promoting role by facilitating the glycolytic process. However, whether and how LDHA regulates cell survival in the nutrient-deficient tumor microenvironment is still unclear. Here, we sought to investigate the role and mechanism of LDHA in regulating cell survival and proliferation under energy stress conditions. Our results showed that the aerobic glycolysis levels, cell survival and proliferation of cervical cancer cells decreased significantly after inhibition of LDHA under normal culture condition while LDHA deficiency greatly inhibited glucose starvation-induced ferroptosis and promoted cell proliferation and tumor formation under energy stress conditions. Mechanistic studies suggested that glucose metabolism shifted from aerobic glycolysis to mitochondrial OXPHOS under energy stress conditions and LDHA knockdown increased accumulation of pyruvate in the cytosol, which entered the mitochondria and upregulated the level of oxaloacetate by phosphoenolpyruvate carboxylase (PC). Importantly, the increase in oxaloacetate production after absence of LDHA remarkably activated AMP-activated protein kinase (AMPK), which increased mitochondrial biogenesis and mitophagy, promoted mitochondrial homeostasis, thereby decreasing ROS level. Moreover, repression of lipogenesis by activation of AMPK led to elevated levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which effectively resisted ROS-induced cell ferroptosis and enhanced cell survival under energy stress conditions. These results suggested that LDHA played an opposing role in survival and proliferation of cervical cancer cells under energy stress conditions, and inhibition of LDHA may not be a suitable treatment strategy for cervical cancer.
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Affiliation(s)
- Chaoran Jia
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China; National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Yulun Wu
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China
| | - Feng Gao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Wei Liu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Na Li
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China
| | - Yao Chen
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China; National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Luguo Sun
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China
| | - Shuyue Wang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Chunlei Yu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China
| | - Yongli Bao
- NMPA Key Laboratory for Quality Control of Cell and Gene Therapy Medicine Products, Northeast Normal University, Changchun, 130024, China.
| | - Zhenbo Song
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130117, China.
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Xuan T. Tripartite Motif-containing Protein 11 Silencing Inhibits Proliferation and Glycolysis and Promotes Apoptosis of Esophageal Squamous Cell Carcinoma Cells by Inactivating Signal Transduction and Activation of Transcription Factor 3/c-Myc Signaling. CHINESE J PHYSIOL 2024; 67:37-46. [PMID: 38780271 DOI: 10.4103/ejpi.ejpi-d-23-00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/10/2023] [Indexed: 05/25/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common type of human digestive tract cancer with poor survival. Tripartite motif-containing protein 11 (TRIM11) is an oncogene in certain cancers that can regulate glycolysis and signal transduction and activation of transcription factor 3 (STAT3) signaling. This study was designed to investigate the role and the mechanism of TRIM11 in ESCC. First, TRIM11 expression in ESCC tissues and the correlation between TRIM11 expression and prognosis were analyzed using bioinformatics tools. After TRIM11 expression was detected by Western blot in ESCC cells, TRIM11 was silenced to evaluate its effect on the malignant phenotypes of ESCC cells. Cell proliferation and apoptosis were assessed by cell counting kit-8 assay, ethynyl-2'- deoxyuridine staining, and flow cytometry, respectively. The glucose uptake and lactate secretion were detected to examine glycolysis. In addition, Western blot was employed to detect the expression of proteins related to apoptosis, glycolysis, and STAT3/c-Myc signaling. Then, ESCC cells were treated with STAT3 activator further to clarify the regulatory effect of TRIM11 on STAT3/c-Myc signaling. TRIM11 was upregulated in ESCC tissues and cells, and high expression of TRIM11 was associated with a poor prognosis. TRIM11 knockdown inhibited the proliferation and glycolysis while facilitating apoptosis of ESCC cells. Besides, the expression of p-STAT3 and c-Myc was significantly downregulated by TRIM11 silencing. Of note, the STAT3 activator partially reversed the effects of TRIM11 depletion on the proliferation, apoptosis, and glycolysis in ESCC cells. Collectively, TRIM11 loss-of-function affects the proliferation, apoptosis, and glycolysis in ESCC cells by inactivating STAT3/c-Myc signaling.
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Affiliation(s)
- Tingting Xuan
- Department of Radiotherapy, The First People's Hospital of Nantong, Nantong, Jiangsu, China
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12
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Zhou X, Wu D, Zhu L, Li R, Yu H, Li W. Withaferin A Inhibits Liver Cancer Tumorigenesis by Suppressing Aerobic Glycolysis through the p53/IDH1/HIF-1α Signaling Axis. Curr Cancer Drug Targets 2024; 24:534-545. [PMID: 38804345 DOI: 10.2174/0115680096262915231026050602] [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: 05/18/2023] [Revised: 08/22/2023] [Accepted: 10/03/2023] [Indexed: 05/29/2024]
Abstract
BACKGROUND The energy supply of certain cancer cells depends on aerobic glycolysis rather than oxidative phosphorylation. Our previous studies have shown that withaferin A (WA), a lactone compound derived from Withania somnifera, suppresses skin carcinogenesis at least partially by stabilizing IDH1 and promoting oxidative phosphorylation. Here, we have extended our studies to evaluate the anti-tumor effect of WA in liver cancer. METHODS Differential expression of glycolysis-related genes between liver cancer tissues and normal tissues and prognosis were verified using an online database. Glycolysis-related protein expression was detected using western blot after overexpression and knockdown of IDH1 and mitochondrial membrane potential assay based on JC-1, and mitochondrial complex I activity was also detected. The inhibitory effect of WA on the biological functions of HepG2 cells was detected along with cell viability using MTT assay, scratch assay, clone formation assay, glucose consumption and lactate production assay. Western blot and qRT-PCR were used to detect the expression of proteins and genes related to IDH1, p53 and HIF1α signaling pathways. RESULTS We first identified that IDH1 expression was downregulated in human liver cancer cells compared to normal liver cells. Next, we found that treatment of HepG2 cells with WA resulted in significantly increased protein levels of IDH1, accompanied by decreased levels of several glycolytic enzymes. Furthermore, we found that WA stabilized IDH1 proteins by inhibiting the degradation by the proteasome. The tumor suppressor p53 was also upregulated by WA treatment, which played a critical role in the upregulation of IDH1 and downregulation of the glycolysis-related genes. Under hypoxic conditions, glycolysis-related genes were induced, which was suppressed by WA treatment, and IDH1 expression was still maintained at higher levels under hypoxia. CONCLUSION Taken together, our results indicated that WA suppresses liver cancer tumorigenesis by p53-mediated IDH1 upregulation, which promotes mitochondrial respiration, thereby inhibiting the HIF-1α pathway and blocking aerobic glycolysis.
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Affiliation(s)
- Xiangyang Zhou
- College of Basic Medicine, Hebei University, Baoding, Hebei, 071000, China
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Hebei University, Baoding, Hebei, 071000, China
| | - Di Wu
- College of Basic Medicine, Hebei University, Baoding, Hebei, 071000, China
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Hebei University, Baoding, Hebei, 071000, China
| | - Linmiao Zhu
- College of Basic Medicine, Hebei University, Baoding, Hebei, 071000, China
| | - Ruohan Li
- College of Basic Medicine, Hebei University, Baoding, Hebei, 071000, China
| | - Haitao Yu
- Department of Biology Genetics, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, China
| | - Wenjuan Li
- College of Basic Medicine, Hebei University, Baoding, Hebei, 071000, China
- Key Laboratory of Pathogenesis Mechanism and Control of Inflammatory-autoimmune Diseases in Hebei Province, Hebei University, Baoding, Hebei, 071000, China
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13
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Tu M, Yin X, Zhuang W, Lin X, Xia Y, Huang Z, Zheng Y, Huang Y. NSG1 promotes glycolytic metabolism to enhance Esophageal squamous cell carcinoma EMT process by upregulating TGF-β. Cell Death Discov 2023; 9:391. [PMID: 37872157 PMCID: PMC10593808 DOI: 10.1038/s41420-023-01694-6] [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: 07/05/2023] [Revised: 10/03/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023] Open
Abstract
As a highly enriched endosomal protein within neuronal cells, NSG1 has been discovered to facilitate the process of epithelial-mesenchymal transition (EMT) in esophageal squamous cell carcinoma (ESCC). However, the precise mechanisms behind this phenomenon have yet to be elucidated. The pivotal role of transforming growth factor-β (TGF-β) in triggering the EMT and its significant contribution towards tumor metabolic reprogramming-responsible for EMT activation-has been robustly established. Nevertheless, the extent of TGF-β involvement in the NSG1-mediated EMT within ESCC and the processes through which metabolic reprogramming participates remain ambiguous. We accessed an array of extensive public genome databases to analyze NSG1 expression in ESCC. Regulation of TGF-β by NSG1 was analyzed by transcriptome sequencing, quantitative Real-Time PCR (qRT-PCR), co-immunoprecipitation (CO-IP), and immunofluorescence (IF). Additionally, cellular functional assays and western blot analyses were conducted to elucidate the effect of NSG1 on TGF-β/Smad signaling pathway, as well as its role in ESCC cell metastasis and proliferation. We validated the influence of the NSG1/TGF-β axis on metabolic reprogramming in ESCC by measuring extracellular acidification, glucose uptake, and lactate production. Our findings identify an oncogenic role for NSG1 in ESCC and show a correlation between high NSG1 expression and poor prognosis in ESCC patients. Additional research indicated TGF-β's involvement in the NSG1-induced EMT process. From a mechanistic perspective, NSG1 upregulates TGF-β, activating the TGF-β/Smad signaling pathway and subsequently fostering the EMT process by inducing cell metabolic reprogramming-evident from elevated glycolysis levels. In conclusion, our study highlights the NSG1/TGF-β axis as a promising therapeutic target for ESCC.
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Affiliation(s)
- Mingshu Tu
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
| | - Xiaoqing Yin
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
- Integrated Chinese and Western Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Wanzhen Zhuang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
| | - Xiaoqing Lin
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
| | - Yu Xia
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
- Integrated Chinese and Western Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Zhixin Huang
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
- Integrated Chinese and Western Medicine College, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yue Zheng
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China
| | - Yi Huang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China.
- Department of Clinical Laboratory, Fujian Provincial Hospital, Fuzhou, China.
- Central Laboratory, Center for Experimental Research in Clinical Medicine, Fujian Provincial Hospital, Fuzhou, China.
- Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Key Laboratory of Cardiovascular Disease, Fuzhou, China.
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14
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Liu Y, Huang N, Qiao X, Gu Z, Wu Y, Li J, Wu C, Li B, Li L. Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism. Int J Oral Sci 2023; 15:37. [PMID: 37661238 PMCID: PMC10475463 DOI: 10.1038/s41368-023-00242-3] [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: 02/08/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023] Open
Abstract
Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.
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Affiliation(s)
- Yunkun Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Nengwen Huang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xianghe Qiao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhiyu Gu
- Department of Preventive and Pediatric Dentistry, Hospital of Stomatology, Zunyi Medical University, Zunyi, China
| | - Yongzhi Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jinjin Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chengzhou Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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15
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Kabir MF, Jackson JL, Fuller AD, Gathuka L, Karami AL, Conde DG, Klochkova A, Mu A, Cai KQ, Klein-Szanto AJ, Muir AB, Whelan KA. Diclofenac exhibits cytotoxic activity associated with metabolic alterations and p53 induction in ESCC cell lines and decreases ESCC tumor burden in vivo. Carcinogenesis 2023; 44:182-195. [PMID: 37014121 PMCID: PMC10215983 DOI: 10.1093/carcin/bgad019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 03/13/2023] [Accepted: 04/03/2023] [Indexed: 04/05/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of human malignancy, often displaying limited therapeutic response. Here, we examine the non-steroidal anti-inflammatory drug diclofenac (DCF) as a novel therapeutic agent in ESCC using complementary in vitro and in vivo models. DCF selectively reduced viability of human ESCC cell lines TE11, KYSE150, and KYSE410 as compared with normal primary or immortalized esophageal keratinocytes. Apoptosis and altered cell cycle profiles were documented in DCF-treated TE11 and KYSE 150. In DCF-treated TE11, RNA-Sequencing identified differentially expressed genes and Ingenuity Pathway Analysis predicted alterations in pathways associated with cellular metabolism and p53 signaling. Downregulation of proteins associated with glycolysis was documented in DCF-treated TE11 and KYSE150. In response to DCF, TE11 cells further displayed reduced levels of ATP, pyruvate, and lactate. Evidence of mitochondrial depolarization and superoxide production was induced by DCF in TE11 and KYSE150. In DCF-treated TE11, the superoxide scavenger MitoTempo improved viability, supporting a role for mitochondrial reactive oxygen species in DCF-mediated toxicity. DCF treatment resulted in increased expression of p53 in TE11 and KYSE150. p53 was further identified as a mediator of DCF-mediated toxicity in TE11 as genetic depletion of p53 partially limited apoptosis in response to DCF. Consistent with the anticancer activity of DCF in vitro, the drug significantly decreased tumor burdene in syngeneic ESCC xenograft tumors and 4-nitroquinoline 1-oxide-mediated ESCC lesions in vivo. These preclinical findings identify DCF as an experimental therapeutic that should be explored further in ESCC.
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Affiliation(s)
- Mohammad Faujul Kabir
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Jazmyne L Jackson
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Annie D Fuller
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Leonny Gathuka
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Adam L Karami
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Don-Gerard Conde
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Alena Klochkova
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Anbin Mu
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
| | - Kathy Q Cai
- Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
| | | | - Amanda B Muir
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Kelly A Whelan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
- Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA
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16
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Macharia JM, Kaposztas Z, Varjas T, Budán F, Zand A, Bodnar I, Bence RL. Targeted lactate dehydrogenase genes silencing in probiotic lactic acid bacteria: A possible paradigm shift in colorectal cancer treatment? Biomed Pharmacother 2023; 160:114371. [PMID: 36758316 DOI: 10.1016/j.biopha.2023.114371] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
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Affiliation(s)
- John M Macharia
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, City of Pẻcs, Hungary.
| | | | - Tímea Varjas
- University of Pẻcs, Medical School, Department of Public Health Medicine, City of Pẻcs, Hungary
| | - Ferenc Budán
- University of Pẻcs, Medical School, Institute of Transdisciplinary Discoveries, City of Pẻcs, Hungary; University of Pécs, Medical School, Institute of Physiology, City of Pécs, Hungary
| | - Afshin Zand
- University of Pẻcs, Medical School, Department of Public Health Medicine, City of Pẻcs, Hungary
| | - Imre Bodnar
- Doctoral School of Health Sciences, Faculty of Health Science, University of Pẻcs, City of Pẻcs, Hungary
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17
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Miholjcic TBS, Halse H, Bonvalet M, Bigorgne A, Rouanne M, Dercle L, Shankar V, Marabelle A. Rationale for LDH-targeted cancer immunotherapy. Eur J Cancer 2023; 181:166-178. [PMID: 36657325 DOI: 10.1016/j.ejca.2022.11.032] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022]
Abstract
Immunotherapies have significantly improved the survival of patients in many cancers over the last decade. However, primary and secondary resistances are encountered in most patients. Unravelling resistance mechanisms to cancer immunotherapies is an area of active investigation. Elevated levels of circulating enzyme lactate dehydrogenase (LDH) have been historically considered in oncology as a marker of bad prognosis, usually attributed to elevated tumour burden and cancer metabolism. Recent evidence suggests that elevated LDH levels could be independent from tumour burden and contain a negative predictive value, which could help in guiding treatment strategies in immuno-oncology. In this review, we decipher the rationale supporting the potential of LDH-targeted therapeutic strategies to tackle the direct immunosuppressive effects of LDH on a wide range of immune cells, and enhance the survival of patients treated with cancer immunotherapies.
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Affiliation(s)
- Tina B S Miholjcic
- Faculté de Médecine, Université de Genève, Genève, Switzerland; Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France
| | - Heloise Halse
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France; INSERM UMR 1163, Imagine Institute, Université de Paris, F-75015 Paris, France
| | - Mélodie Bonvalet
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France
| | - Amélie Bigorgne
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France; INSERM UMR 1163, Imagine Institute, Université de Paris, F-75015 Paris, France
| | - Mathieu Rouanne
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France; Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Département d'Urologie, Hôpital Foch, UVSQ, Université Paris-Saclay, 92150 Suresnes, France
| | - Laurent Dercle
- Department of Radiology, New York Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA
| | - Vishnu Shankar
- Immunology Program, School of Medicine, Stanford University, CA, USA
| | - Aurélien Marabelle
- Laboratoire de Recherche Translationnelle en Immunothérapie (LRTI), INSERM U1015, Gustave Roussy, Villejuif, France; Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, 94805 Villejuif, France; Centre d'Investigation Clinique BIOTHERIS, INSERM CIC1428, Gustave Roussy, Villejuif, France; Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
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18
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The Role of Reprogrammed Glucose Metabolism in Cancer. Metabolites 2023; 13:metabo13030345. [PMID: 36984785 PMCID: PMC10051753 DOI: 10.3390/metabo13030345] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
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19
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Zhu Y, Wu F, Hu J, Xu Y, Zhang J, Li Y, Lin Y, Liu X. LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion. FASEB J 2023; 37:e22744. [PMID: 36583693 DOI: 10.1096/fj.202201219rr] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/05/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022]
Abstract
Dysregulated trophoblast proliferation, invasion, and apoptosis may cause several pregnancy-associated complications, such as unexplained recurrent spontaneous abortion (URSA). Recent studies have shown that metabolic abnormalities, including glycolysis inhibition, may dysregulate trophoblast function, leading to URSA. However, the underlying mechanisms remain unclear. Herein, we found that lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, was significantly reduced in the placental villus of URSA patients. The human trophoblast cell line HTR-8/SVneo was used to investigate the possible LDHA-mediated regulation of trophoblast function. LDHA knockdown in HTR-8/SVneo cells induced G0/G1 phase arrest and increased apoptosis, whereas LDHA overexpression reversed these effects. Next, RNA sequencing combined with Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the PI3K/AKT signaling pathway is potentially affected by downstream genes of LDHA. Especially, we found that LDHA knockdown decreased the phosphorylation levels of PI3K, AKT, and FOXO1, resulting in a significant downregulation of CyclinD1. In addition, treatment with an AKT inhibitor or FOXO1 inhibitor also verified that the PI3K/AKT/FOXO1 signaling pathway influenced the gene expression of CyclinD1 in trophoblast. Moreover, p-AKT expression correlated positively with LDHA expression in syncytiotrophoblasts and extravillous trophoblasts in first-trimester villus. Collectively, this study revealed a new regulatory pathway for LDHA/PI3K/AKT/FOXO1/CyclinD1 in the trophoblast cell cycle and proliferation.
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Affiliation(s)
- Yueyue Zhu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fan Wu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianing Hu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yichi Xu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinwen Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Li
- Center for Reproductive Medicine, Shandong University, Jinan, China
| | - Yi Lin
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaorui Liu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.,Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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20
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Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers. Int J Mol Sci 2022; 23:ijms232416062. [PMID: 36555705 PMCID: PMC9785069 DOI: 10.3390/ijms232416062] [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: 09/26/2022] [Revised: 12/11/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients.
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21
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Ahmed SS, Rahman MO, Alqahtani AS, Sultana N, Almarfadi OM, Ali MA, Lee J. Anticancer potential of phytochemicals from Oroxylum indicum targeting Lactate Dehydrogenase A through bioinformatic approach. Toxicol Rep 2022; 10:56-75. [PMID: 36583135 PMCID: PMC9792705 DOI: 10.1016/j.toxrep.2022.12.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/04/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
In recent years, small molecule inhibition of LDHA (Lactate Dehydrogenase A) has evolved as an appealing option for anticancer therapy. LDHA catalyzes the interconversion of pyruvate and lactate in the glycolysis pathway to play a crucial role in aerobic glycolysis. Therefore, in the current investigation LDHA was targeted with bioactive phytochemicals of an ethnomedicinally important plant species Oroxylum indicum (L.) Kurz. A total of 52 phytochemicals were screened against LDHA protein through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) assay and molecular dynamics simulation to reveal three potential lead compounds such as Chrysin-7-O-glucuronide (-8.2 kcal/mol), Oroxindin (-8.1 kcal/mol) and Oroxin A (-8.0 kcal/mol). ADMET assay unveiled favorable pharmacokinetic, pharmacodynamic and toxicity properties for all the lead compounds. Molecular dynamics simulation exhibited significant conformational stability and compactness. MM/GBSA free binding energy calculations further corroborated the selection of top candidates where Oroxindin (-46.47 kcal/mol) was found to be better than Chrysin-7-O-glucuronide (-45.72 kcal/mol) and Oroxin A (-37.25 kcal/mol). Aldolase reductase and Xanthine dehydrogenase enzymes were found as potential drug targets and Esculin, the FDA approved drug was identified as structurally analogous to Oroxindin. These results could drive in establishing novel medications targeting LDHA to fight cancer.
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Affiliation(s)
| | - M. Oliur Rahman
- Department of Botany, University of Dhaka, Dhaka 1000, Bangladesh,Corresponding author.
| | - Ali S. Alqahtani
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - Nahid Sultana
- Department of Botany, Jagannath University, Dhaka 1100, Bangladesh
| | - Omer M. Almarfadi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
| | - M. Ajmal Ali
- Deperment of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Joongku Lee
- Department of Environment and Forest Resources, Chungnam National University, Daehak-ro, Yuseong-gu, Daejeon, Republic of Korea
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22
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An Update on the Metabolic Landscape of Oncogenic Viruses. Cancers (Basel) 2022; 14:cancers14235742. [PMID: 36497226 PMCID: PMC9738352 DOI: 10.3390/cancers14235742] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/17/2022] [Indexed: 11/24/2022] Open
Abstract
Viruses play an important role in cancer development as about 12% of cancer types are linked to viral infections. Viruses that induce cellular transformation are known as oncoviruses. Although the mechanisms of viral oncogenesis differ between viruses, all oncogenic viruses share the ability to establish persistent chronic infections with no obvious symptoms for years. During these prolonged infections, oncogenic viruses manipulate cell signaling pathways that control cell cycle progression, apoptosis, inflammation, and metabolism. Importantly, it seems that most oncoviruses depend on these changes for their persistence and amplification. Metabolic changes induced by oncoviruses share many common features with cancer metabolism. Indeed, viruses, like proliferating cancer cells, require increased biosynthetic precursors for virion production, need to balance cellular redox homeostasis, and need to ensure host cell survival in a given tissue microenvironment. Thus, like for cancer cells, viral replication and persistence of infected cells frequently depend on metabolic changes. Here, we draw parallels between metabolic changes observed in cancers or induced by oncoviruses, with a focus on pathways involved in the regulation of glucose, lipid, and amino acids. We describe whether and how oncoviruses depend on metabolic changes, with the perspective of targeting them for antiviral and onco-therapeutic approaches in the context of viral infections.
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23
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Pouysségur J, Marchiq I, Parks SK, Durivault J, Ždralević M, Vucetic M. 'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives. Semin Cancer Biol 2022; 86:334-346. [PMID: 35820598 DOI: 10.1016/j.semcancer.2022.07.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 12/16/2022]
Abstract
The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e., MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumor microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumors (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumor growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumor growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
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Affiliation(s)
- J Pouysségur
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France; Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco.
| | - I Marchiq
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France.
| | - S K Parks
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco.
| | - J Durivault
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco
| | - M Ždralević
- University Côte d'Azur, (IRCAN), CNRS, INSERM, Centre A, Lacassagne, 06189 Nice, France.
| | - M Vucetic
- Department of Medical Biology, Centre Scientifique de Monaco (CSM), 98000 Monaco
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24
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Xia H, Huang Z, Xu Y, Yam JWP, Cui Y. Reprogramming of central carbon metabolism in hepatocellular carcinoma. Biomed Pharmacother 2022; 153:113485. [DOI: 10.1016/j.biopha.2022.113485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/20/2022] [Accepted: 07/27/2022] [Indexed: 11/02/2022] Open
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25
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Bagué S, León X, Terra X, Lejeune M, Camacho M, Avilés‐Jurado F. Prognostic capacity of the transcriptional expression of lactate dehydrogenase A in patients with head and neck squamous cell carcinoma. Head Neck 2022; 44:2505-2512. [DOI: 10.1002/hed.27161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/10/2022] [Accepted: 07/15/2022] [Indexed: 11/10/2022] Open
Affiliation(s)
- Silvia Bagué
- Pathology Department, Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain
| | - Xavier León
- Otorhinolaryngology Department, Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain
- Centro de Investigación Biomédica en Red de Bioingeniería Biomateriales y Nanomedicina (CIBER‐BBN) Madrid Spain
| | - Ximena Terra
- MoBioFood Research Group, Biochemistry and Biotechnology Department Universitat Rovira i Virgili, Campus Sescel·lades Tarragona Spain
| | - Marylène Lejeune
- Pathology Department, Plataforma de Estudios Histológicos, Citológicos y de Digitalización, Hospital de Tortosa Verge de la Cinta Institut d'Investigació Sanitària Pere Virgili (IISPV), URV Tortosa Spain
| | - Mercedes Camacho
- Genomics of Complex Diseases Research Institute Hospital Sant Pau Barcelona Spain
| | - Francesc‐Xavier Avilés‐Jurado
- Otorhinolaryngology Department, Hospital Universitari Joan XXIII, Institut d´investigació Sanitària Pere Virgili IISPV, Universitat Rovira i Virgili URV Tarragona Spain
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26
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Inhibiting Warburg Effect Can Suppress the Biological Activity and Secretion Function of Keloid Fibroblasts. Aesthetic Plast Surg 2022; 46:1964-1972. [PMID: 35595921 DOI: 10.1007/s00266-022-02899-3] [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: 01/14/2022] [Accepted: 03/31/2022] [Indexed: 11/01/2022]
Abstract
BACKGROUND Keloids have always been a difficult problem in the clinic. In our previous study, we demonstrated a Warburg effect in keloid fibroblasts (KFs), like tumors. In this study, we aimed to investigate the effects of the suppression of the Warburg effect on the biological activity and function of KFs. METHODS KFs were isolated and cultured with different concentrations of oxamate, a classical competitive lactate dehydrogenase A (LDHA) inhibitor. First, the suppression effect of oxamate on the Warburg effect in KFs was verified. After treatment with oxamate, a scratch wound assay, real-time PCR, flow cytometry, CCK8 kit, and western blotting were used to detect the migration ability, collagen production, apoptosis, cell proliferation, cell cycle distribution, and related molecular mechanisms in KFs. RESULTS As expected, oxamate inhibited the Warburg effect in KFs in a dose-dependent manner. After the inhibition of the Warburg effect in KFs, the cell migration rate decreased significantly, the mRNA transcription levels of type I collagen and α-SMA were significantly lower, the cell apoptosis rate increased significantly, the cell proliferation activity decreased significantly, and G0/G1 phase cells in KFs increased significantly. The expression of cyclin D1 and its upstream regulatory factors, Akt protein and GSK3 β (phospho S9), decreased significantly. CONCLUSION Inhibiting the Warburg effect in KFs significantly suppressed cell proliferation, enhanced cell apoptosis, inhibited cell migration ability, reduced collagen secretion, and induced G0/G1 arrest through the Akt-GSK3β-Cyclin D1 pathway. Therefore, inhibiting the Warburg effect in KFs may provide a new option for the prevention and treatment of keloids. LEVEL OF EVIDENCE IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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27
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Tan H, Wang H, Ma J, Deng H, He Q, Chen Q, Zhang Q. Identification of human LDHC4 as a potential target for anticancer drug discovery. Acta Pharm Sin B 2022; 12:2348-2357. [PMID: 35646544 PMCID: PMC9136605 DOI: 10.1016/j.apsb.2021.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/07/2021] [Accepted: 11/08/2021] [Indexed: 11/25/2022] Open
Abstract
One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.
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28
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Zhao L, Liu Y, Zhang S, Wei L, Cheng H, Wang J, Wang J. Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer. Cell Death Dis 2022; 13:378. [PMID: 35444235 PMCID: PMC9021207 DOI: 10.1038/s41419-022-04821-w] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023]
Abstract
Metabolic disorders and abnormal immune function changes occur in tumor tissues and cells to varying degrees. There is increasing evidence that reprogrammed energy metabolism contributes to the development of tumor suppressive immune microenvironment and influences the course of gastric cancer (GC). Current studies have found that tumor microenvironment (TME) also has important clinicopathological significance in predicting prognosis and therapeutic efficacy. Novel approaches targeting TME therapy, such as immune checkpoint blockade (ICB), metabolic inhibitors and key enzymes of immune metabolism, have been involved in the treatment of GC. However, the interaction between GC cells metabolism and immune metabolism and how to make better use of these immunotherapy methods in the complex TME in GC are still being explored. Here, we discuss how metabolic reprogramming of GC cells and immune cells involved in GC immune responses modulate anti-tumor immune responses, as well as the effects of gastrointestinal flora in TME and GC. It is also proposed how to enhance anti-tumor immune response by understanding the targeted metabolism of these metabolic reprogramming to provide direction for the treatment and prognosis of GC.
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Affiliation(s)
- Lin Zhao
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Yuanyuan Liu
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Simiao Zhang
- The First Clinical College, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Lingyu Wei
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.,Key Laboratory of Esophageal Cancer Basic Research and Clinical Transformation, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Hongbing Cheng
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.,Department of Microbiology, Changzhi Medical College, Changzhi, Shanxi, 046000, China
| | - Jinsheng Wang
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China. .,Key Laboratory of Esophageal Cancer Basic Research and Clinical Transformation, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, 046000, China.
| | - Jia Wang
- Collaborative Innovation Center for Aging Mechanism Research and Transformation, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China. .,Department of Immunology, Center for Healthy Aging, Changzhi Medical College, Changzhi, Shanxi, 046000, China.
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29
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LINC01128 facilitates the progression of pancreatic cancer through up-regulation of LDHA by targeting miR-561-5p. Cancer Cell Int 2022; 22:93. [PMID: 35193567 PMCID: PMC8862213 DOI: 10.1186/s12935-022-02490-5] [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: 09/18/2021] [Accepted: 01/24/2022] [Indexed: 12/24/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) regulate tumor development and metastasis in several types of cancers through various molecular mechanisms. However, the biological role of most lncRNAs in pancreatic cancer (PC) remains unclear. Here, we explored the expression, biological functions, and molecular mechanism of LINC01128 in PC. Methods Quantitive reverse transcription PCR was used to detect the expression level of LINC01128 in PC tissues and different PC cell lines. A loss-of-function and gain-of-function experiment was used to explore the biological effects of LINC01128 on PC carcinogenesis in vitro and in vivo. Western blot analysis, subcellular fractionation experiment, luciferase reporter gene assay, and MS2-RNA immunoprecipitation experiment were used to study the potential molecular mechanism of LINC01128 during carcinogenesis. Results The expression of LINC01128 was upregulated in PC tissues and cell lines, and overexpression of LINC01128 was significantly related to the poor prognosis of patients with PC. Furthermore, silencing LINC01128 significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of PC cells in vitro and tumor growth in vivo, while LINC01128 overexpression promoted these processes. Further research showed that LINC01128 acted as a sponge for microRNA miR-561-5p, and lactate dehydrogenase A (LDHA) was the downstream target gene of miR-561-5p. It was also revealed that the expression of miR-561-5p in PC was decreased, and a negative correlation between miR-561-5p and LINC01128 was revealed. Based on rescue experiments, LDHA overexpression partially restored the inhibitory effect of LINC01128 knockdown on proliferation, migration, and invasion of PC cells. Conclusions LINC01128 promotes the proliferation, migration, invasion, and EMT of PC by regulating the miR-561-5p/LDHA axis, suggesting LINC01128 may be a new prognostic marker and therapeutic target in PC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02490-5.
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30
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Cheng Y, Ma Z, Liu S, Yang X, Li S. CircLPAR3 knockdown suppresses esophageal squamous cell carcinoma cell oncogenic phenotypes and Warburg effect through miR-873-5p/LDHA axis. Hum Exp Toxicol 2022; 41:9603271221143695. [PMID: 36484173 DOI: 10.1177/09603271221143695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Circular RNAs (circRNAs) have been identified to participate in regulating multiple malignancies. Herein, this study aimed to explore the clinical significance, biological function, and regulatory mechanisms of circRNA lysophosphatidic acid receptor 3 (circLPAR3) in esophageal squamous cell carcinoma (ESCC) cell malignant phenotypes and Warburg effect. METHODS The qRT-PCR and Western blot were used to detect the levels of genes and proteins. Glucose uptake and lactate production were detected to determine the Warburg effect. The effects of circLPAR3 on ESCC cell proliferation, apoptosis, and metastasis were evaluated by MTT, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, wound healing, and transwell assays. The binding interaction between miR-873-5p and circLPAR3 or lactate dehydrogenase A (LDHA) was verified using dual-luciferase reporter and RIP assays. Xenograft mice models were established to conduct in vivo analysis. RESULTS CircLPAR3 is a stable circRNA and was increased in ESCC tissues and cells. Functionally, circLPAR3 knockdown suppressed ESCC cell Warburg effect, proliferation, metastasis, and induced apoptosis in vitro, and impeded xenograft tumor growth and Warburg effect in ESCC mice models. Mechanistically, circLPAR3 served as a sponge for miR-873-5p, which targeted LDHA. Moreover, circLPAR3 could regulate LDHA expression by sponging miR-873-5p. Thereafter, rescue experiments suggested that miR-873-5p inhibition reversed the anticancer effects of circLPAR3 silencing on ESCC cells. Furthermore, miR-873-5p overexpression restrained ESCC cell Warburg effect and oncogenic phenotypes, which were abolished by LDHA up-regulation. CONCLUSION CircLPAR3 knockdown suppressed ESCC cell growth, metastasis, and Warburg effect by miR-873-5p/LDHA axis, implying a promising molecular target for ESCC therapy.
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Affiliation(s)
- Yao Cheng
- Department of Thoracic Surgery, 12480Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhenchuan Ma
- Department of Thoracic Surgery, 12480Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shiyuan Liu
- Department of Thoracic Surgery, 12480Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoping Yang
- Department of Thoracic Surgery, 12480Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shaomin Li
- Department of Thoracic Surgery, 12480Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Ghasemishahrestani Z, Melo Mattos LM, Tilli TM, Santos ALSD, Pereira MD. Pieces of the Complex Puzzle of Cancer Cell Energy Metabolism: An Overview of Energy Metabolism and Alternatives for Targeted Cancer Therapy. Curr Med Chem 2021; 28:3514-3534. [PMID: 32814521 DOI: 10.2174/0929867327999200819123357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 11/22/2022]
Abstract
Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called the 'Warburg effect'. Currently, it has been accepted that the Warburg effect is not compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused on the bioenergetic and biosynthetic pathways in order to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrates, amino acids and lipids have already been reported for cancer cells and this might play an important role in cancer progression. To the best of our knowledge, these changes are mainly attributed to genetic reprogramming which leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes that are highly relevant for cellular energy are targets of oncogenes (e.g. PI3K, HIF1, and Myc) and tumor suppressor proteins (e.g. p53). As a consequence of extensive studies on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, in addition to influencing genetic reprogramming in cancer cells. In this review, we present an overview of cancer cell metabolism (carbohydrate, amino acid, and lipid), and also describe oncogenes and tumor suppressors that directly affect the metabolism. We also discuss some of the potential therapeutic candidates which have been designed to target and disrupt the main driving forces associated with cancer cell metabolism and proliferation.
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Affiliation(s)
- Zeinab Ghasemishahrestani
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Maura Melo Mattos
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tatiana Martins Tilli
- Centro de Desenvolvimento Tecnologico em Saude, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
| | - André Luis Souza Dos Santos
- Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Dias Pereira
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Bel’skaya LV, Sarf EA, Kosenok VK. Survival Rates of Patients with Non-Small Cell Lung Cancer Depending on Lymph Node Metastasis: A Focus on Saliva. Diagnostics (Basel) 2021; 11:diagnostics11050912. [PMID: 34065406 PMCID: PMC8161301 DOI: 10.3390/diagnostics11050912] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/26/2021] [Accepted: 05/19/2021] [Indexed: 12/25/2022] Open
Abstract
The aim of this study was to compare overall survival (OS) rates at different pN stages of NSCLC depending on tumor characteristics and to assess the applicability of saliva biochemical markers as prognostic signs. The study included 239 patients with NSCLC (pN0-120, pN1-51, pN2-68). Saliva was analyzed for 34 biochemical indicators before the start of treatment. For pN0, the tumor size does not have a prognostic effect, but the histological type should be taken into account. For pN1 and pN2, long-term results are significantly worse in squamous cell cancer with a large tumor size. A larger volume of surgical treatment reduces the differences between OS. The statistically significant factors of an unfavorable prognosis at pN0 are the lactate dehydrogenase activity <1294 U/L and the level of diene conjugates >3.97 c.u. (HR = 3.48, 95% CI 1.21-9.85, p = 0.01541); at pN1, the content of imidazole compounds >0.296 mmol/L (HR = 6.75, 95% CI 1.28-34.57, p = 0.00822); at pN2 levels of protein <0.583 g/L and Schiff bases >0.602 c.u., as well as protein >0.583 g/L and Schiff bases <0.602 c.u. (HR = 2.07, 95% CI 1.47-8.93, p = 0.04351). Using salivary biochemical indicators, it is possible to carry out stratification into prognostic groups depending on the lymph node metastasis.
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Affiliation(s)
- Lyudmila V. Bel’skaya
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
- Correspondence: or
| | - Elena A. Sarf
- Biochemistry Research Laboratory, Omsk State Pedagogical University, 644099 Omsk, Russia;
| | - Victor K. Kosenok
- Department of Oncology, Omsk State Medical University, 644099 Omsk, Russia;
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Al-Salam S, Kandhan K, Sudhadevi M. Down regulation of lactate dehydrogenase initiates apoptosis in HeLa and MCF-7 cancer cells through increased voltage-dependent anion channel protein and inhibition of BCL2. Oncotarget 2021; 12:923-935. [PMID: 33953846 PMCID: PMC8092341 DOI: 10.18632/oncotarget.27950] [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: 02/23/2021] [Accepted: 03/25/2021] [Indexed: 11/25/2022] Open
Abstract
Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect, where pyruvate is converted to lactate, by enzyme lactate dehydrogenase A (LDH-A). In this study, we have investigated the effect of inhibition of LDH-A on cells viability and identifying the mechanism of cell death in HeLa and MCF-7 cancer cells. Human cervical cancer HeLa cell line and breast cancer MCF-7 cell line were used to investigate the effect of inhibition of LDH-A by sodium oxamate on cell survival and proliferation using western blot, spectrophotometry, and immunofluorescent study. There was significant reduction in LDH-A (P < 0.001) and cell viability (P < 0.001) in a dose-dependent mode in both HeLa and MCF-7 SO-treated cancer cells. The voltage-dependent anion channel (VDAC) protein was significantly increased (P < 0.001) in association with decreased LDH-A. The proapoptotic proteins; cytochrome C (P < 0.001), BAX (P < 0.001), cleaved caspase-3 (P < 0.001), cleaved caspase-8 (P < 0.001), and cleaved caspase-9 (P < 0.001) were significantly increased in association with decreased LDH-A. While, the anti-apoptotic protein Bcl2 was significantly decreased (P < 0.001) in association with decreased LDH-A. We conclude that Inhibition of LDH-A can decrease cells viability through activation of intrinsic apoptotic pathway via increased VDAC protein and inhibition of Bcl2 as well as activation of the extrinsic apoptotic pathway through activation of caspase-8.
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Affiliation(s)
- Suhail Al-Salam
- Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, AlAin, UAE
| | - Karthishwaran Kandhan
- Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, AlAin, UAE
| | - Manjusha Sudhadevi
- Department of Pathology, College of Medicine & Health Sciences, United Arab Emirates University, AlAin, UAE
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Nadal-Bufi F, Mason JM, Chan LY, Craik DJ, Kaas Q, Troeira Henriques S. Designed β-Hairpins Inhibit LDH5 Oligomerization and Enzymatic Activity. J Med Chem 2021; 64:3767-3779. [PMID: 33765386 DOI: 10.1021/acs.jmedchem.0c01898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lactate dehydrogenase 5 (LDH5) is overexpressed in metastatic tumors and is an attractive target for anticancer therapy. Small-molecule drugs have been developed to target the substrate/cofactor sites of LDH5, but none has reached the clinic to date, and alternative strategies remain almost unexplored. Combining rational and computer-based approaches, we identified peptidic sequences with high affinity toward a β-sheet region that is involved in protein-protein interactions (PPIs) required for the activity of LDH5. To improve stability and potency, these sequences were grafted into a cyclic cell-penetrating β-hairpin peptide scaffold. The lead grafted peptide, cGmC9, inhibited LDH5 activity in vitro in low micromolar range and more efficiently than the small-molecule inhibitor GNE-140. cGmC9 inhibits LDH5 by targeting an interface unlikely to be inhibited by small-molecule drugs. This lead will guide the development of new LDH5 inhibitors and challenges the landscape of drug discovery programs exclusively dedicated to small molecules.
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Affiliation(s)
- Ferran Nadal-Bufi
- School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Queensland 4102, Australia
| | - Jody M Mason
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom
| | - Lai Yue Chan
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - David J Craik
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Quentin Kaas
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Sónia Troeira Henriques
- School of Biomedical Sciences, Translational Research Institute, Queensland University of Technology, Brisbane, Queensland 4102, Australia
- Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia
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Hayes C, Donohoe CL, Davern M, Donlon NE. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment. Cancer Lett 2021; 500:75-86. [PMID: 33347908 DOI: 10.1016/j.canlet.2020.12.021] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/08/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022]
Abstract
The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.
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Affiliation(s)
- Conall Hayes
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Claire L Donohoe
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Maria Davern
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland
| | - Noel E Donlon
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin, Ireland; Trinity St James' Cancer Institute, St James's Hospital Dublin, Ireland.
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Ban EJ, Kim D, Kim JK, Kang SW, Lee J, Jeong JJ, Nam KH, Chung WY, Kim K. Lactate Dehydrogenase A as a Potential New Biomarker for Thyroid Cancer. Endocrinol Metab (Seoul) 2021; 36:96-105. [PMID: 33677931 PMCID: PMC7937852 DOI: 10.3803/enm.2020.819] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 12/31/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Several cancers show increased levels of lactate dehydrogenase A (LDHA), which are associated with cancer progression. However, it remains unclear whether LDHA levels are associated with papillary thyroid cancer (PTC) aggressiveness or with the presence of the PTC prognostic marker, the BRAFV600E mutation. This study aimed to evaluate the potential of LDHA as a PTC prognostic marker. METHODS LDHA expression was examined in 83 PTC tissue specimens by immunohistochemistry. Human thyroid cell lines were genetically manipulated to overexpress BRAFV600E or were treated with a BRAF-specific short hairpin RNA (shBRAF), whose effects on LDHA expression were evaluated by Western blotting. Data from 465 PTC patients were obtained from The Cancer Genome Atlas (TCGA) database and analyzed to validate the in vitro results. RESULTS LDHA was aberrantly overexpressed in PTC. Intense immunostaining for LDHA was observed in PTC specimens carrying mutated BRAF, whereas the intensity was less in wild-type BRAF samples. Overexpression of BRAFV600E resulted in LDHA upregulation, whereas treatment with shBRAF downregulated LDHA in human thyroid cell lines. Furthermore, LDHA mRNA expression was significantly elevated and associated with BRAFV600E expression in thyroid cancer tissues from TCGA database. Additionally, LDHA overexpression was found to be correlated with aggressive clinical features of PTC, such as lymph node metastases and advanced tumor stages. CONCLUSION LDHA overexpression is associated with the BRAFV600E mutation and an aggressive PTC behavior. Therefore, LDHA may serve as a biomarker and therapeutic target in PTC.
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Affiliation(s)
- Eun Jeong Ban
- Department of Surgery, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
- Department of Surgery, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Daham Kim
- Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Kyong Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Sang-Wook Kang
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jandee Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Ju Jeong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Kee-Hyun Nam
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Woong Youn Chung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Kunhong Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Korea
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Targeting Cancer Metabolism and Current Anti-Cancer Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:15-48. [PMID: 33725343 DOI: 10.1007/978-3-030-55035-6_2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Several studies have exploited the metabolic hallmarks that distinguish between normal and cancer cells, aiming at identifying specific targets of anti-cancer drugs. It has become apparent that metabolic flexibility allows cancer cells to survive during high anabolic demand or the depletion of nutrients and oxygen. Cancers can reprogram their metabolism to the microenvironments by increasing aerobic glycolysis to maximize ATP production, increasing glutaminolysis and anabolic pathways to support bioenergetic and biosynthetic demand during rapid proliferation. The increased key regulatory enzymes that support the relevant pathways allow us to design small molecules which can specifically block activities of these enzymes, preventing growth and metastasis of tumors. In this review, we discuss metabolic adaptation in cancers and highlight the crucial metabolic enzymes involved, specifically those involved in aerobic glycolysis, glutaminolysis, de novo fatty acid synthesis, and bioenergetic pathways. Furthermore, we also review the success and the pitfalls of the current anti-cancer drugs which have been applied in pre-clinical and clinical studies.
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Du P, Liao Y, Zhao H, Zhang J, Mu K. ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis. Cell Signal 2020; 74:109718. [PMID: 32707073 DOI: 10.1016/j.cellsig.2020.109718] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Aerobic glycolysis is a unique tumor cell phenotype considered as one of the hallmarks of cancer. Aerobic glycolysis can accelerate tumor development by increasing glucose uptake and lactate production. In the present study, lactate dehydrogenase A (LDHA) is significantly increased within glioma tissue samples and cells, further confirming the oncogenic role of LDHA within glioma. METHODS Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were applied for histopathological examination. The protein levels of LDHA, transporter isoform 1 (GLUT1), hexokinase 2 (HK2), phosphofructokinase (PFK) in target cells were detected by Immunoblotting. The predicted miR-9 binding to lncRNA Annexin A2 Pseudogene 2 (ANXA2P2) or the 3' untranslated region (UTR) of LDHA was verified using Luciferase reporter assay. Cell viability or apoptosis were examined by MTT assay or Flow cytometry. Intracellular glucose and Lactate levels were measured using glucose assay kit and lactate colorimetric assay kit. RESULTS The expression of ANXA2P2 showed to be dramatically upregulated within glioma tissue samples and cells. Knocking down ANXA2P2 within glioma cells significantly inhibited cell proliferation and aerobic glycolysis, as manifested as decreased lactate and increased glucose in culture medium, and downregulated protein levels of glycolysis markers, GLUT1, HK2, PFK, as well as LDHA. miR-9 was predicted to target both lncRNA ANXA2P2 and LDHA. The overexpression of miR-9 suppressed the cell proliferation and aerobic glycolysis of glioma cells. Notably, miR-9 could directly bind to LDHA 3'UTR to inhibit LDHA expression and decrease the protein levels of LDHA. ANXA2P2 competitively targeted miR-9, therefore counteracting miR-9-mediated repression on LDHA. Within tissues, miR-9 exhibited a negative correlation with ANXA2P2 and LDHA, respectively, whereas ANXA2P2 and LDHA exhibited a positive correlation with each other. CONCLUSIONS In conclusion, ANXA2P2/miR-9/LDHA axis modulates the aerobic glycolysis progression in glioma cells, therefore affecting glioma cell proliferation.
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Affiliation(s)
- Peng Du
- Department of Neurosurgery, Xiangya Hospital, The Central South University, Changsha 410008, PR China; Department of Neurosurgery, The Second Affiliated Hospital, Xinjiang Medical University, Urumqi 830063, PR China
| | - Yiwei Liao
- Department of Neurosurgery, Xiangya Hospital, The Central South University, Changsha 410008, PR China.
| | - Haiting Zhao
- Department of Neurology, Xiangya Hospital, The Central South University, Changsha 410008, PR China
| | - Jingjing Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Xinjiang Medical University, Urumqi 830063, PR China
| | - Kere Mu
- Department of Neurosurgery, The Second Affiliated Hospital, Xinjiang Medical University, Urumqi 830063, PR China
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Luan Y, Zhang W, Xie J, Mao J. CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway. Clin Transl Oncol 2020; 23:222-228. [DOI: 10.1007/s12094-020-02409-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/23/2020] [Indexed: 12/19/2022]
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Baltazar F, Afonso J, Costa M, Granja S. Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy. Front Oncol 2020; 10:231. [PMID: 32257942 PMCID: PMC7093491 DOI: 10.3389/fonc.2020.00231] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/11/2020] [Indexed: 12/16/2022] Open
Abstract
To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.
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Affiliation(s)
- Fátima Baltazar
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Julieta Afonso
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Marta Costa
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Sara Granja
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
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Al-Azzam N. Sirtuin 6 and metabolic genes interplay in Warburg effect in cancers. J Clin Biochem Nutr 2020; 66:169-175. [PMID: 32523242 DOI: 10.3164/jcbn.19-110] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 12/13/2019] [Indexed: 01/10/2023] Open
Abstract
Under oxygen availability, normal cells undergo mitochondrial oxidative phosphorylation to metabolize glucose and yield up to 36 ATPs per glucose molecule for cellular functions, and undergo non-oxidative metabolism (glycolysis) under hypoxic and proliferating conditions to yield 2 ATP per glucose. These cells metabolize glucose to pyruvate via glycolysis followed by conversion of pyruvate to lactate via lactate dehydrogenase. However, cancer cells have the ability to undergo glycolysis and ferment glucose to lactate regardless of oxygen availability; a phenomenon first addressed by Otto Warburg and called, "Warburg effect". Numerous glycolytic genes/proteins have been identified in tumors; that include glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase-M2 splice isoform (PKM2), and lactate dehydrogenase (LDH-A). Histone deacetylase sirtuin 6 (SIRT6), an epigenetic regulator, is highly expressed in various cancers. SIRT6 plays an important role in Warburg effect by regulating many glycolytic genes. Loss of SIRT6 enhances tumor growth via enhancing glycolysis. This review is mainly concerned with exploring the most recent advances in understanding the roles of the metabolic genes (GLUT1, HK2, PKM2, and LDH-A) and the epigenetic regulator SIRT6 in cancer metabolism and how SIRT6 can modulate these metabolic genes expression and its possible use as a therapeutic target for cancer treatment.
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Affiliation(s)
- Nosayba Al-Azzam
- Department of Physiology and Biochemistry, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan
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Mizuno Y, Hattori K, Taniguchi K, Tanaka K, Uchiyama K, Hirose Y. Intratumoral heterogeneity of glutaminase and lactate dehydrogenase A protein expression in colorectal cancer. Oncol Lett 2020; 19:2934-2942. [PMID: 32218849 PMCID: PMC7068422 DOI: 10.3892/ol.2020.11390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 01/21/2020] [Indexed: 12/17/2022] Open
Abstract
The high expression of metabolic enzymes, including glutaminase (GA) and lactate dehydrogenase A (LDHA), which contribute to bioenergetics and biosynthesis of mammalian cells, has been identified in a variety of cancer types. The current study indicated intratumoral heterogeneity with respect to protein expression of the metabolic enzymes in colorectal cancer (CRC). GA protein expression was determined using immunohistochemistry in 98 cases of surgically resected T3 CRC. A total of 75 cases (74%) exhibited moderate to strong immunopositivity of GA based on whole-section examination. A significant correlation was demonstrated between GA expression and clinicopathological features, including histological type and tumor budding in a patient population. Detailed histological analysis revealed the upregulation of GA protein expression at the invasive margin, including tumor budding of CRC tissues. Semi-quantitative examination revealed a significant difference in immunoexpression level of GA between the invasive margin and central CRC. However, LDHA expression exhibited an opposite pattern, with expression elevated at the center and significantly decreased at the tumors invasive margin. Immunohistochemical expression of another glycolytic enzyme hexokinase II was equivalent in both regions. Furthermore, gene silencing of GLS1, which encodes GA protein, and GA inhibitor treatment significantly inhibited cell growth of CRC cell lines. Therefore, the results of the present study demonstrated that the alteration in GA and LDHA expression is more prominent at the invasive margin, which involves tumor budding in CRC.
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Affiliation(s)
- Yuta Mizuno
- Department of Pathology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.,Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Kimiaki Hattori
- Department of Pathology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Kohei Taniguchi
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.,Department of Translational Research Program, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Keitaro Tanaka
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Kazuhisa Uchiyama
- Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yoshinobu Hirose
- Department of Pathology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
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Khan AA, Allemailem KS, Alhumaydhi FA, Gowder SJT, Rahmani AH. The Biochemical and Clinical Perspectives of Lactate Dehydrogenase: An Enzyme of Active Metabolism. Endocr Metab Immune Disord Drug Targets 2020; 20:855-868. [PMID: 31886754 DOI: 10.2174/1871530320666191230141110] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 11/05/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These diverse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well. OBJECTIVE The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases. METHODS With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents. DISCUSSION LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have diversified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases. CONCLUSION LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.
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Affiliation(s)
- Amjad A Khan
- Department of Basic Health Sciences, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Khaled S Allemailem
- Department of Basic Health Sciences, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
| | - Sivakumar J T Gowder
- Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City,
Vietnam
- Faculty of Applied Sciences, Ton Duc Thang University, Vietnam
| | - Arshad H Rahmani
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Qassim, Saudi Arabia
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Guo J, Zhao P, Liu Z, Li Z, Yuan Y, Zhang X, Yu Z, Fang J, Xiao K. MiR-204-3p Inhibited the Proliferation of Bladder Cancer Cells via Modulating Lactate Dehydrogenase-Mediated Glycolysis. Front Oncol 2019; 9:1242. [PMID: 31850191 PMCID: PMC6895070 DOI: 10.3389/fonc.2019.01242] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/29/2019] [Indexed: 11/13/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs that negatively regulate the expression of downstream targeted mRNAs. Increasing evidence has suggested that miRNAs act as tumor suppressors or oncogenes to interfere the progression of cancers. Here, we showed that miR-204-3p was decreased in bladder cancer tissues and cell lines. Down-regulation of miR-204-3p was significantly associated with a poor prognosis in bladder cancer patients. Overexpression of miR-204-3p inhibited proliferation and induced apoptosis in bladder cancer cells. Furthermore, miR-204-3p was found to bind to the 3′-untranslated region (UTR) of the lactate dehydrogenase (LDHA), which consequently reduced the expression of both mRNA and protein of LDHA. Interestingly, overexpression of miR-204-3p decreased glucose consumption and lactate production of bladder cancer cells. Overexpression of LDHA relieved the growth inhibition and cell apoptosis enhancement by miR-204-3p in bladder cancer cells. These results demonstrated that miR-204-3p negatively modulated the proliferation of bladder cancer cells via targeting LDHA-mediated glycolysis. MiR-204-3p might be a promising candidate for designing anticancer medication.
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Affiliation(s)
- Jinan Guo
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Pan Zhao
- Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Clinical Medical Research Center, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical School of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Zengqin Liu
- Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Clinical Medical Research Center, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical School of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Zaishang Li
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Yeqing Yuan
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Xueqi Zhang
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Zhou Yu
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Jiequn Fang
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
| | - Kefeng Xiao
- Department of Urology, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China.,Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen Urology Minimally Invasive Engineering Center, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen, China
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Yeung C, Gibson AE, Issaq SH, Oshima N, Baumgart JT, Edessa LD, Rai G, Urban DJ, Johnson MS, Benavides GA, Squadrito GL, Yohe ME, Lei H, Eldridge S, Hamre J, Dowdy T, Ruiz-Rodado V, Lita A, Mendoza A, Shern JF, Larion M, Helman LJ, Stott GM, Krishna MC, Hall MD, Darley-Usmar V, Neckers LM, Heske CM. Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma. Cancer Res 2019; 79:5060-5073. [PMID: 31431459 PMCID: PMC6774872 DOI: 10.1158/0008-5472.can-19-0217] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 06/26/2019] [Accepted: 08/12/2019] [Indexed: 12/15/2022]
Abstract
Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis. SIGNIFICANCE: LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma.
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Affiliation(s)
- Choh Yeung
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Anna E Gibson
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sameer H Issaq
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Nobu Oshima
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Joshua T Baumgart
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Leah D Edessa
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Ganesha Rai
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Daniel J Urban
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Michelle S Johnson
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gloria A Benavides
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Giuseppe L Squadrito
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Marielle E Yohe
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Haiyan Lei
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sandy Eldridge
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - John Hamre
- Laboratory of Investigative Toxicology, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Tyrone Dowdy
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Victor Ruiz-Rodado
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Adrian Lita
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Arnulfo Mendoza
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jack F Shern
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Mioara Larion
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Lee J Helman
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Gordon M Stott
- Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Murali C Krishna
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Matthew D Hall
- Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Victor Darley-Usmar
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Leonard M Neckers
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Christine M Heske
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Yoneten KK, Kasap M, Akpinar G, Gunes A, Gurel B, Utkan NZ. Comparative Proteome Analysis of Breast Cancer Tissues Highlights the Importance of Glycerol-3-phosphate Dehydrogenase 1 and Monoacylglycerol Lipase in Breast Cancer Metabolism. Cancer Genomics Proteomics 2019; 16:377-397. [PMID: 31467232 PMCID: PMC6727073 DOI: 10.21873/cgp.20143] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 05/17/2019] [Accepted: 05/30/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIM Breast cancer (BC) incidence and mortality rates have been increasing due to the lack of appropriate diagnostic tools for early detection. Proteomics-based studies may provide novel targets for early diagnosis and efficient treatment. The aim of this study was to investigate the global changes occurring in protein profiles in breast cancer tissues to discover potential diagnostic or prognostic biomarkers. MATERIALS AND METHODS BC tissues and their corresponding healthy counterparts were collected, subtyped, and subjected to comparative proteomics analyses using two-dimensional gel electrophoresis (2-DE) and two-dimensional electrophoresis fluorescence difference gel (DIGE) coupled to matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF/TOF) to explore BC metabolism at the proteome level. Western blot analysis was used to verify changes occurring at the protein levels. RESULTS Bioinformatics analyses performed with differentially regulated proteins highlighted the changes occurring in triacylglyceride (TAG) metabolism, and directed our attention to TAG metabolism-associated proteins, namely glycerol-3-phosphate dehydrogenase 1 (GPD1) and monoacylglycerol lipase (MAGL). These proteins were down-regulated in tumor groups in comparison to controls. CONCLUSION GPD1 and MAGL might be promising tissue-based protein biomarkers with a predictive potential for BC.
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Affiliation(s)
| | - Murat Kasap
- Department of Medical Biology, Kocaeli University Medical School, Kocaeli, Turkey
| | - Gurler Akpinar
- Department of Medical Biology, Kocaeli University Medical School, Kocaeli, Turkey
| | - Abdullah Gunes
- Department of General Surgery, Derince Education and Application Hospital, Kocaeli, Turkey
| | - Bora Gurel
- Department of Pathology, Kocaeli University Medical School, Kocaeli, Turkey
| | - Nihat Zafer Utkan
- Department of General Surgery, Kocaeli University Medical School, Kocaeli, Turkey
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Ovarian cancer-derived exosomes promote tumour metastasis in vivo: an effect modulated by the invasiveness capacity of their originating cells. Clin Sci (Lond) 2019; 133:1401-1419. [PMID: 31227603 DOI: 10.1042/cs20190082] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 06/05/2019] [Accepted: 06/21/2019] [Indexed: 12/13/2022]
Abstract
Exosomes are small nanovesicles that carry bioactive molecules which can be delivered to neighbouring cells to modify their biological functions. Studies have showed that exosomes from ovarian cancer (OVCA) cells can alter the cell migration and proliferation of cells within the tumour microenvironment, an effect modulated by the invasiveness capacity of their originating cells. Using an OVCA cell line xenograph mouse model, we showed that exosomes derived from a high invasiveness capacity cell line (exo-SKOV-3) promoted metastasis in vivo compared with exosomes from a low invasiveness capacity cell line (exo-OVCAR-3). Analysis from anin vivo imaging system (IVIS) revealed that exo-SKOV-3 formed metastatic niches, whereas exo-OVCAR-3 formed colonies of clustered cells close to the site of injection. Interestingly, kinetic parameters showed that the half-maximal stimulatory time (ST50) of tumour growth with exo-OVCAR-3 (4.0 ± 0.31 weeks) was significantly lower compared with the ST50 in mice injected with exo-SKOV-3 (4.5 ± 0.32 weeks). However, the number of metastic nodes in mice injected with exo-SKOV-3 was higher compared with exo-OVCAR-3. Using a quantitative mass spectrometry approach (SWATH MS/MS) followed by bioinformatics analysis using the Ingenuity Pathway Analysis (IPA), we identified a total of 771 proteins. Furthermore, 40 of these proteins were differentially expressed in tumour tissues from mice injected with exo-SKOV-3 compared with exo-OVCAR-3, and associated with Wnt canonical pathway (β-catenin). Finally, we identified a set of proteins which had elevated expression in the circulating exosomes in association with tumour metastasis. These observations suggest that exosomal signalling plays an important role in OVCA metastasis.
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Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med 2018; 7:6124-6136. [PMID: 30403008 PMCID: PMC6308051 DOI: 10.1002/cam4.1820] [Citation(s) in RCA: 421] [Impact Index Per Article: 60.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/15/2018] [Accepted: 09/18/2018] [Indexed: 12/14/2022] Open
Abstract
Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio-characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.
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Affiliation(s)
- Yangbo Feng
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Yanlu Xiong
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Tianyun Qiao
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular BiologyFourth Military Medical UniversityXi'anChina
| | - Yong Han
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
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Ma ZJ, Yan H, Wang YJ, Yang Y, Li XB, Shi AC, Jing-Wen X, Yu-Bao L, Li L, Wang XX. Proteomics analysis demonstrating rosmarinic acid suppresses cell growth by blocking the glycolytic pathway in human HepG2 cells. Biomed Pharmacother 2018; 105:334-349. [PMID: 29864622 DOI: 10.1016/j.biopha.2018.05.129] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 05/12/2018] [Accepted: 05/24/2018] [Indexed: 12/24/2022] Open
Abstract
Rosmarinic acid (RA), isolated from herbal balm mint plants, has demonstrated potent anti-tumor properties against liver cancer. However, the precise underlying mechanisms remain unclear. This study aimed to investigate the molecular mechanisms of RA in HepG2 cells. RA anti-tumor activity was assessed using 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays, and Hoechst 33258 staining. Apoptosis and the cell cycle distribution were evaluated by flow cytometry. A proteomics approach was used to identify differentially expressed proteins following RA treatment in HepG2 cells, and quantitative reverse transcription-quantitative polymerase chain reaction was used to validate the results. Bioinformatics analysis was also implemented to further understand the identified proteins, and western blotting was used to analyze the associated proteins. Our results suggested that RA treatment significantly inhibits the viability of HepG2 cells. The MTT and LDH assays indicated dose-dependent decreases in cell proliferation following RA treatment. Hoechst 33258 staining and flow cytometry analysis showed that RA exhibits an apoptosis-inducing effect and induces cell cycle arrest in G1. The proteomics analysis successfully identified 16 differentially expressed proteins. Bioinformatics analysis indicated that the identified proteins participated in several biological processes and exhibited various molecular functions, mainly related to inactivation of the glycolytic pathway. Further western blotting analysis showed that RA could downregulate the expression of glucose transporter-1 and hexokinase-2, leading to the suppression of glucose consumption and generation of lactate and ATP. Taken together, our study found that RA exhibits significant cytotoxic effects by inhibiting cell proliferation and inducing apoptosis and cell cycle arrest, possibly by blocking the glycolytic pathway in human HepG2 cells.
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Affiliation(s)
- Zhan-Jun Ma
- The Second Clinical School, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Hu Yan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Ya-Jiao Wang
- Clinical College of Hebei Medical University, Shijiazhuang, Hebei, 050031, China
| | - Yang Yang
- The Second Clinical School, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Xiao-Bin Li
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - An-Cheng Shi
- The Second Clinical School, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Xu Jing-Wen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Lu Yu-Bao
- The Second Clinical School, Lanzhou University, Lanzhou, Gansu, 730000, China
| | - Lu Li
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000, China
| | - Xue-Xi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000, China.
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50
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Chen D, Chen W, Xu Y, Zhu M, Xiao Y, Shen Y, Zhu S, Cao C, Xu X. Upregulated immune checkpoint HHLA2 in clear cell renal cell carcinoma: a novel prognostic biomarker and potential therapeutic target. J Med Genet 2018; 56:43-49. [PMID: 29967134 DOI: 10.1136/jmedgenet-2018-105454] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/29/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is a malignant urogenital cancer with high mortality; however, current progress in understanding its molecular mechanism and predicting clinical treatment outcome is limited. Therefore, this study is to evaluate the clinical significance of immune inhibitory molecular human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) in ccRCC prognosis and transcriptional regulatory network. METHODS Expression of HHLA2 in ccRCC was examined by an online database platform ONCOMINE. The ONCOMINE result was independently validated by qRT-PCR and immunohistochemistry. Kaplan-Meier survival was generated using IBM SPSS Statistics V.22. ccRCC tissues cells with high HHLA2 were sorted and subjected to microarray transcriptional profiling and analysis. RESULTS It was shown that expression of HHLA2 was statistically significantly increased in ccRCC tissues compared with normal renal tissues at both transcriptional and protein level. Moreover, the expression of HHLA2 was closely correlated with multiple clinicopathological features including tumour size, clinical stage and histological grade. High HHLA2 expression was associated with poor overall survival and clinical outcome. Comprehensive microarray analysis further identified thousands of HHLA2 targets including mRNA, long non-coding RNA and circular RNA that might function in various biological processes, especially, immune response. CONCLUSION Increased HHLA2 expression was observed in ccRCC tumour tissue, which leads to a remarkable shorter overall survival and poorer prognosis. Together with other molecular evidence, we have demonstrated that HHLA2 could be a potential prognostic biomarker for ccRCC.
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Affiliation(s)
- Dongming Chen
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Chen
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Xu
- Department of Nephrology, Huai'an Second People's Hospital and the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Meng Zhu
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Xiao
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Yanhao Shen
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Shuai Zhu
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Changchun Cao
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Xianlin Xu
- Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
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