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Kamli H, Khan NU. Revolutionising cancer intervention: the repercussions of CAR-T cell therapy on modern oncology practices. Med Oncol 2025; 42:228. [PMID: 40448746 DOI: 10.1007/s12032-025-02783-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 05/12/2025] [Indexed: 06/02/2025]
Abstract
Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking advance in oncology, leveraging patient-specific immune cells to target malignant tumours precisely. By equipping T cells with synthetic receptors, CAR-T therapy achieves remarkable antitumor effects and offers hope for durable cancer control. However, several limitations persist, including antigen scarcity, immunosuppressive tumour microenvironments, and T-cell exhaustion. CRISPR-Cas9 gene editing has enhanced CAR-T potency by knocking out immune checkpoints (PD-1, CTLA-4) and improving persistence, while RNA interference (RNAi) silences immune-evasion genes (e.g. SOCS1). Nanozyme-based delivery systems enable precise CRISPR-Cas9 delivery (> 70% editing efficiency) and tumour targeting, overcoming instability and off-target effects. Innovations like SUPRA CARs, armoured CAR-T cells (e.g. IL-12/IL-21-secreting TRUCKs), and dual checkpoint inhibition synergize to reprogram the tumour microenvironment, reducing relapse by 40% in trials. Despite progress, high costs, manufacturing hurdles, and ethical concerns (e.g. germline editing risks) remain critical barriers. Emerging solutions include universal off-the-shelf CAR-Ts, hybrid nano-CRISPR systems, and AI-driven design, paving the way for scalable, personalised immunotherapy. This review highlights breakthroughs in CRISPR, RNAi, and nanotechnology, underscoring CAR-T therapy's transformative potential while addressing translational challenges for broader clinical adoption.
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Affiliation(s)
- Hossam Kamli
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
| | - Najeeb Ullah Khan
- Institute of Biotechnology and Genetic Engineering, The University of Agriculture, Peshawar, 25130, Pakistan.
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Wen ZH, Wu ZS, Cheng HJ, Huang SY, Tang SH, Teng WN, Su FW, Chen NF, Sung CS. Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins. Mol Neurobiol 2025; 62:246-263. [PMID: 38837104 DOI: 10.1007/s12035-024-04254-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/21/2024] [Indexed: 06/06/2024]
Abstract
Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.
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Affiliation(s)
- Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan
| | - Zong-Sheng Wu
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan
| | - Hao-Jung Cheng
- Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan
| | - Shi-Ying Huang
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, 361021, China
| | - Shih-Hsuan Tang
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan
| | - Wei-Nung Teng
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan
| | - Fu-Wei Su
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan
| | - Nan-Fu Chen
- Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan
| | - Chun-Sung Sung
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan.
- School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan.
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Stepanov Y, Kolesnik D, Yakshibaeva Y, Solyanik G. EFFECT OF ADHESIVE LLC CELL PRETREATMENT BY OXAMATE ON THE SURVIVAL INDEXES AFTER TRANSITION TO DE-ADHESIVE GROWTH. Exp Oncol 2024; 46:237-243. [PMID: 39704457 DOI: 10.15407/exp-oncology.2024.03.237] [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: 12/19/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND The ability to metabolic reprogramming is a distinctive feature of metastatically active tumor cells. A classic example of metabolic reprogramming, characteristic of almost all malignant cells, is aerobic glycolysis. Therefore, inhibition of glycolysis in tumor cells is considered a promising strategy for antitumor therapy. AIM To generate Lewis lung carcinoma (LLC) cell subpopulation after pretreatment by a lactate dehydrogenase (LDH) inhibitor - oxamate in adhesive growth conditions, and then to study the metabolism of this subpopulation in the anchorage-independent growth conditions. MATERIALS AND METHODS LLC cells were cultured without oxamate or with 17 mM oxamate in the adhesive growth conditions with the following transition to the anchorage-independent growth conditions without oxamate. A distribution of LLC cells by cell cycle phases, apoptosis rate, levels of reactive oxygen species (ROS), E-cadherin, and vimentin were determined by flow cytometry. Glucose consumption and lactate production were determined by spectrophotometry. RESULTS 48-h oxamate treatment in adhesive growth conditions resulted in a 30% decrease of the total number of LLC cells compared to the control. In 72 h after the transfer of both oxamate-treated and control cells into the anchorage-independent growth condition without oxamate, the number of viable cells pretreated with oxamate was reduced by 17% (p < 0.05) compared to the control cells. However, the distribution of cells by cell cycle phases did not differ. In cells pre-treated with oxamate, the rate of glucose consumption decreased by 20% (p < 0.05), ROS generation was reduced by 17%, vimentin expression decreased by 10% while the rate of lactate production was the same in oxamate-pretreated and control cells. CONCLUSION The cytostatic effect of oxamate demonstrated in adhesive growth conditions persisted for 72 h in the anchorage-independent growth conditions. The absence of differences in the cell cycle phase distribution and a decrease in the ROS generation may indicate the initial stage of overcoming the cytostatic effect of oxamate after 72 h of culturing LLC cells in anchorage- independent growth conditions.
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Affiliation(s)
- Yu Stepanov
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - D Kolesnik
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Yu Yakshibaeva
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - G Solyanik
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine
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Wang L, Zhang L, Dunmall LC, Wang YY, Fan Z, Cheng Z, Wang Y. The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors. Cancer Lett 2024; 591:216871. [PMID: 38604310 DOI: 10.1016/j.canlet.2024.216871] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/26/2024] [Accepted: 04/06/2024] [Indexed: 04/13/2024]
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing an increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to as "living drugs" as they not only target tumor cells directly, but also induce long-term immune memory that has the potential to provide long-lasting protection. CD19.CAR-T cells have achieved complete response rates of over 90 % for acute lymphoblastic leukemia and over 60 % for non-Hodgkin's lymphoma. However, the response rate of CAR-T cells in the treatment of solid tumors remains extremely low and the side effects potentially severe. In this review, we discuss the limitations that the solid tumor microenvironment poses for CAR-T application and the solutions that are being developed to address these limitations, in the hope that in the near future, CAR-T cell therapy for solid tumors can attain the same success rates as are now being seen clinically for hematological malignancies.
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Affiliation(s)
- Lihong Wang
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China; National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lufang Zhang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Louisa Chard Dunmall
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Yang Yang Wang
- Department of General Pediatrics, Newham General Hospital, E13 8SL, London, United Kingdom
| | - Zaiwen Fan
- Department of Oncology, Air Force Medical Center, PLA, Beijing, China
| | - Zhenguo Cheng
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yaohe Wang
- National Centre for International Research in Cell and Gene Therapy, Sino British Research Centre for Molecular Oncology, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China; Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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Shi Z, Hu C, Zheng X, Sun C, Li Q. Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells. Exp Hematol Oncol 2024; 13:55. [PMID: 38778409 PMCID: PMC11110349 DOI: 10.1186/s40164-024-00519-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Radiotherapy is one of the mainstream approaches for cancer treatment, although the clinical outcomes are limited due to the radioresistance of tumor cells. Hypoxia and metabolic reprogramming are the hallmarks of tumor initiation and progression and are closely linked to radioresistance. Inside a tumor, the rate of angiogenesis lags behind cell proliferation, and the underdevelopment and abnormal functions of blood vessels in some loci result in oxygen deficiency in cancer cells, i.e., hypoxia. This prevents radiation from effectively eliminating the hypoxic cancer cells. Cancer cells switch to glycolysis as the main source of energy, a phenomenon known as the Warburg effect, to sustain their rapid proliferation rates. Therefore, pathways involved in metabolic reprogramming and hypoxia-induced radioresistance are promising intervention targets for cancer treatment. In this review, we discussed the mechanisms and pathways underlying radioresistance due to hypoxia and metabolic reprogramming in detail, including DNA repair, role of cancer stem cells, oxidative stress relief, autophagy regulation, angiogenesis and immune escape. In addition, we proposed the existence of a feedback loop between energy metabolic reprogramming and hypoxia, which is associated with the development and exacerbation of radioresistance in tumors. Simultaneous blockade of this feedback loop and other tumor-specific targets can be an effective approach to overcome radioresistance of cancer cells. This comprehensive overview provides new insights into the mechanisms underlying tumor radiosensitivity and progression.
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Affiliation(s)
- Zheng Shi
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Cuilan Hu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaogang Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
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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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Salken I, Provencio JJ, Coulibaly AP. A potential therapeutic target: The role of neutrophils in the central nervous system. Brain Behav Immun Health 2023; 33:100688. [PMID: 37767236 PMCID: PMC10520304 DOI: 10.1016/j.bbih.2023.100688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 09/14/2023] [Accepted: 09/16/2023] [Indexed: 09/29/2023] Open
Abstract
Neutrophils play a critical role in immune defense as the first recruited and most abundant leukocytes in the innate immune system. As such, regulation of neutrophil effector functions have strong implications on immunity. These cells display a wide heterogeneity of function, including both inflammatory and immunomodulatory roles. Neutrophils commonly infiltrate the central nervous system (CNS) in response to varied pathological conditions. There is still little understanding of the role these cells play in the CNS in such conditions. In the present review, we will summarize what is known of neutrophil's role in cancer and Alzheimer's disease (AD), with a focus on highlighting the gaps in our understanding.
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Affiliation(s)
- Isabel Salken
- College of Arts and Science, University of Virginia, USA
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Huang Q, Li S, Chen X, He C, Chen Y, Huang Y, Liu Y, Wang Y, Zheng X. Association between serum lactate dehydrogenase and lymph node metastasis in cervical cancer. Oncol Lett 2023; 26:482. [PMID: 37818132 PMCID: PMC10561153 DOI: 10.3892/ol.2023.14069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 08/11/2023] [Indexed: 10/12/2023] Open
Abstract
The aim of the present study was to evaluate the association between serum lactate dehydrogenase (LDH) and the risk of lymph node metastasis (LNM) in the International Federation of Gynecology and Obstetrics (FIGO) 2009 cervical cancer (CC) stages IB1-IIA2. All patient medical records with FIGO 2009 stage IB1-IIA2 CC between January 2012 and January 2022 were analyzed retrospectively. The association between serum LDH and LNM was assessed using uni- and multivariate logistic regression analyses, subgroup analyses and P-splines. The present study included 586 patients, 91 (15.5%) of whom had LNM. Patients with an elevated LDH level were more likely to have a deep stromal invasion, lymph-vascular space invasion, LNM and to be of an older age. Multivariate logistic regression revealed a significant association between LNM and LDH levels. After adjusting for age, FIGO stage, tumor markers and risk factors according to the Sedlis criteria, patients in the highest LDH quartile had an increased risk of LNM compared with those in the lowest LDH quartile (odds ratio, 3.5; 95% CI, 1.57-7.81). Furthermore, P-spline regression revealed a dependence of LNM on LDH. The predictive value of LDH level remained significant in the subgroup analysis. The present study suggested that a higher LDH level was independently associated with CC and LNM, and that LDH level may serve as a potential tumor marker and treatment-related indicator.
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Affiliation(s)
- Qiuyuan Huang
- Department of Radiation Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Suyu Li
- Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Xiaoying Chen
- Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Chenqiang He
- Department of Radiation Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Youlin Chen
- Department of Radiation Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yangbi Huang
- Department of Radiation Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yiqun Liu
- Department of Radiation Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Yanglin Wang
- The Social Public Relations Sector, Fujian Province Blood Center, Fuzhou, Fujian 350001, P.R. China
| | - Xiangqin Zheng
- Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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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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Crookenden MA, Burke CR, Mitchell MD, Phyn CVC, Roche JR, Heiser A. Effect of nonsteroidal anti-inflammatory drugs on the inflammatory response of bovine endometrial epithelial cells in vitro. J Dairy Sci 2023; 106:2651-2666. [PMID: 36653292 DOI: 10.3168/jds.2021-21742] [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: 05/01/2021] [Accepted: 09/30/2022] [Indexed: 01/19/2023]
Abstract
Chronic postpartum uterine infection detrimentally affects subsequent fertility. Nonsteroidal anti-inflammatory drugs (NSAID) are used to alleviate pain and treat inflammatory conditions in transition dairy cows with varying success. To screen the efficacy of NSAID in the absence of animal experiments, we have established an in vitro model to study uterine inflammation. Inflammation was induced in cultured bovine endometrial epithelial cells by challenging cells with an inflammation cocktail: lipopolysaccharide and proinflammatory cytokines, interleukin-1β (IL1β) and tumor necrosis factor α (TNFα). Release of the inflammation markers, serum amyloid A (SAA) and α-1-acid glycoprotein (αAGP), was measured by ELISA. Concentration of these markers was used to indicate the effectiveness in dampening inflammation of 5 NSAID: meloxicam, flunixin meglumine, aspirin, ketoprofen, and tolfenamic acid. Three NSAID, meloxicam, flunixin meglumine, and tolfenamic acid, were successful at dampening the release of SAA and αAGP into cell-culture supernatant, and the corresponding treated cells were selected for down-stream mRNA expression analysis. Expression of 192 genes involved in regulation of inflammatory pathways were investigated using Nanostring. Of the genes investigated, 81 were above the mRNA expression-analysis threshold criteria and were included in expression analysis. All SAA genes investigated (SAA2, SAA3, M-SAA3.2) were upregulated in response to the inflammation cocktail, relative to mRNA expression in control cells; however, AGP mRNA expression was below the expression analysis threshold and was, therefore, excluded from analysis. Treatment with NSAID downregulated genes involved in regulating chemokine signaling (e.g., CXCL2, CXCR4, CXCL5, and CXCL16) and genes that regulate the eicosanoid pathway (e.g., LTA4H, PTGS2, PLA2G4A, and PTGDS). Of the 5 NSAID investigated, meloxicam, flunixin meglumine, and tolfenamic acid are recommended for further investigation into treatment of postpartum uterine inflammation. The results from this study confirm the immunomodulatory properties of the endometrial epithelium in response to inflammatory stimuli and suggest that NSAID may be beneficial in alleviating uterine inflammation.
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Affiliation(s)
- M A Crookenden
- Hopkirk Research Institute, AgResearch, Palmerston North 4442, New Zealand.
| | - C R Burke
- DairyNZ Ltd., Private Bag 3221, Hamilton 3240, New Zealand
| | - M D Mitchell
- Institute of Health and Biomedical Innovation - Centre for Children's Health Research, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, 4101, Australia
| | - C V C Phyn
- DairyNZ Ltd., Private Bag 3221, Hamilton 3240, New Zealand
| | - J R Roche
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand
| | - A Heiser
- Hopkirk Research Institute, AgResearch, Palmerston North 4442, New Zealand
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11
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Sun N, Kabir M, Lee Y, Xie L, Hu X, Velez J, Chen X, Kaniskan HÜ, Jin J. Discovery of the First Lactate Dehydrogenase Proteolysis Targeting Chimera Degrader for the Treatment of Pancreatic Cancer. J Med Chem 2023; 66:596-610. [PMID: 36538511 PMCID: PMC9969998 DOI: 10.1021/acs.jmedchem.2c01505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA and LDHB are two main LDH subunits, and both are frequently overexpressed in tumors and essential for tumor growth. A number of LDHA/B small-molecule inhibitors have been developed. Here, we report the discovery of the first LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105). 22 potently degraded LDHA in a time- and ubiquitin-proteasome system-dependent manner. Using an unbiased global proteomic study, we confirmed that 22 degraded both LDHA and LDHB significantly. 22 was significantly more potent than the parent LDH inhibitor in suppressing the growth of both quasi-mesenchymal state and epithelial state pancreatic cancer cell lines. Furthermore, 22 was bioavailable in mice through intraperitoneal injection. Overall, 22 could be a valuable chemical tool for the research community to explore pathophysiological functions of LDH in vitro and in vivo.
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Affiliation(s)
- Ning Sun
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Md Kabir
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Youngeun Lee
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Ling Xie
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Xiaoping Hu
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Julia Velez
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Xian Chen
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - H Ümit Kaniskan
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
| | - Jian Jin
- Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
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12
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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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13
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Abstract
High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically improved outcomes in patients with melanoma over the past decade, provide only marginal benefit to those with high serum LDH levels. When viewed separately from the oncological, biochemical, biological and immunological perspectives, serum LDH is often interpreted in very different ways. Oncologists usually see high serum LDH only as a robust biomarker of a poor prognosis, and biochemists are aware of the complexity of the various LDH isoforms and of their key roles in cancer metabolism, whereas LDH is typically considered to be oncogenic and/or immunosuppressive by cancer biologists and immunologists. Integrating these various viewpoints shows that the regulation of the five LDH isoforms, and their enzymatic and non-enzymatic functions is closely related to key oncological processes. In this Review, we highlight that serum LDH is far more than a simple indicator of tumour burden; it is a complex biomarker associated with the activation of several oncogenic signalling pathways as well as with the metabolic activity, invasiveness and immunogenicity of many tumours, and constitutes an extremely attractive target for cancer therapy.
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14
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Oudaert I, Van der Vreken A, Maes A, De Bruyne E, De Veirman K, Vanderkerken K, Menu E. Metabolic cross-talk within the bone marrow milieu: focus on multiple myeloma. Exp Hematol Oncol 2022; 11:49. [PMID: 36050788 PMCID: PMC9438316 DOI: 10.1186/s40164-022-00303-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer cells are well-known for their capacity to adapt their metabolism to their increasing energy demands which is necessary for tumor progression. This is no different for Multiple Myeloma (MM), a hematological cancer which develops in the bone marrow (BM), whereby the malignant plasma cells accumulate and impair normal BM functions. It has become clear that the hypoxic BM environment contributes to metabolic rewiring of the MM cells, including changes in metabolite levels, increased/decreased activity of metabolic enzymes and metabolic shifts. These adaptations will lead to a pro-tumoral environment stimulating MM growth and drug resistance In this review, we discuss the identified metabolic changes in MM and the BM microenvironment and summarize how these identified changes have been targeted (by inhibitors, genetic approaches or deprivation studies) in order to block MM progression and survival.
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Affiliation(s)
- Inge Oudaert
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Arne Van der Vreken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Anke Maes
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Elke De Bruyne
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Kim De Veirman
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Karin Vanderkerken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium
| | - Eline Menu
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090, Brussels, Belgium.
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15
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Fan N, Fu H, Feng X, Chen Y, Wang J, Wu Y, Bian Y, Li Y. Long non-coding RNAs play an important regulatory role in tumorigenesis and tumor progression through aerobic glycolysis. Front Mol Biosci 2022; 9:941653. [PMID: 36072431 PMCID: PMC9441491 DOI: 10.3389/fmolb.2022.941653] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Compared to normal cells, cancer cells generate ATP mainly through aerobic glycolysis, which promotes tumorigenesis and tumor progression. Long non-coding RNAs (LncRNAs) are a class of transcripts longer than 200 nucleotides with little or without evident protein-encoding function. LncRNAs are involved in the ten hallmarks of cancer, interestingly, they are also closely associated with aerobic glycolysis. However, the mechanism of this process is non-transparent to date. Demonstrating the mechanism of lncRNAs regulating tumorigenesis and tumor progression through aerobic glycolysis is particularly critical for cancer therapy, and may provide novel therapeutic targets or strategies in cancer treatment. In this review, we discuss the role of lncRNAs and aerobic glycolysis in tumorigenesis and tumor progression, and further explore their interaction, in hope to provide a novel therapeutic target for cancer treatment.
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Affiliation(s)
- Ni Fan
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hui Fu
- College of Integrated Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuchen Feng
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yatong Chen
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingyu Wang
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuqi Wu
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuhong Bian
- College of Integrated Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Yuhong Bian, ; Yingpeng Li,
| | - Yingpeng Li
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Yuhong Bian, ; Yingpeng Li,
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16
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Herheliuk TS, Perepelytsina OM, Chmelnytska YM, Kuznetsova GM, Dzjubenko NV, Raksha NG, Gorbach OI, Sydorenko MV. Study of Cancer Stem Cell Subpopulations in Breast Cancer Models. CYTOL GENET+ 2022. [DOI: 10.3103/s0095452722040041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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17
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Yang D, Yin J, Shan L, Yi X, Zhang W, Ding Y. Identification of lysine-lactylated substrates in gastric cancer cells. iScience 2022; 25:104630. [PMID: 35800753 PMCID: PMC9253728 DOI: 10.1016/j.isci.2022.104630] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/26/2022] [Accepted: 06/13/2022] [Indexed: 11/30/2022] Open
Affiliation(s)
- Dawei Yang
- Department of Pharmacy, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210003, China
| | - Jie Yin
- Department of General Surgery, Haian People’s Hospital, Haian, Jiangsu 226600, China
| | - Liuqun Shan
- Department of General Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210003, China
| | - Xingling Yi
- Micron Biotechnology Co., Ltd., Hangzhou 310051, China
| | - Wei Zhang
- Department of General Surgery, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Corresponding author
| | - Yongbin Ding
- Department of General Surgery, Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital), Nanjing, Jiangsu 211800, China
- Department of General Surgery, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210003, China
- Corresponding author
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18
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Vallée A. Curcumin and Wnt/β‑catenin signaling in exudative age‑related macular degeneration (Review). Int J Mol Med 2022; 49:79. [PMID: 35445729 PMCID: PMC9083851 DOI: 10.3892/ijmm.2022.5135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/11/2022] [Indexed: 11/06/2022] Open
Abstract
Curcumin is a natural product widely used due to its pharmacological effects. Nevertheless, only a limited number of studies concerning the effects of curcumin on exudative age‑related macular degeneration (AMD) is currently available. Since ophthalmic diseases, including exudative AMD, have a marked impact on public health, the prevention and therapy of ophthalmic disorders remain of increasing concern. Exudative AMD is characterized by choroidal neovascularization (CNV) invading the subretinal space, ultimately enhancing exudation and hemorrhaging. The exudative AMD subtype corresponds to 10 to 15% of cases of macular degeneration; however, the occurrence of this subtype has been reported as the major cause of vision loss and blindness, with the occurrence of CNV being responsible for 80% of the cases with vision loss. In CNV increased expression of VEGF has been observed, stimulated by the overactivation of Wnt/β‑catenin signaling pathway. The stimulation of the Wnt/β‑catenin signaling pathway is responsible for the activation of several cellular mechanisms, simultaneously enhancing inflammation, oxidative stress and angiogenesis in numerous diseases, including ophthalmic disorders. Some studies have previously demonstrated the possible advantage of the use of curcumin for the inhibition of Wnt/β‑catenin signaling. In the present review article, the different mechanisms of curcumin are described concerning its effects on oxidative stress, inflammation and angiogenesis in exudative AMD, by interacting with Wnt/β‑catenin signaling.
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Affiliation(s)
- Alexandre Vallée
- Department of Epidemiology-Data-Biostatistics, Delegation of Clinical Research and Innovation (DRCI), Foch Hospital, 92150 Suresnes, France
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19
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Ye Y, Chen M, Chen X, Xiao J, Liao L, Lin F. Clinical Significance and Prognostic Value of Lactate Dehydrogenase Expression in Cervical Cancer. Genet Test Mol Biomarkers 2022; 26:107-117. [PMID: 35349377 PMCID: PMC8982136 DOI: 10.1089/gtmb.2021.0006] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background: Lactate dehydrogenase (LDH) is a marker of injury and disease as it is expressed extensively in numerous cell types and tissues. Moreover it is released during tissue breakdown, and is elevated in cancerous tissues. However, the clinical significance and prognostic value of LDH as a tumor marker have been subject to considerable discussion. Objective: In this study, clinical serum LDH data from patients with cervical cancer (CC), CC microarray data, and RNA-seq data were integrated to assess the expression of LDH in CC. Methods: A total of 204 patients with newly diagnosed CC and 204 age-matched healthy controls were included to evaluate serum LDH levels in CC and non-cancer samples. External microarrays and RNA-seq datasets were collected for the differential expression analysis of LDH in CC and non-cancer tissue samples. Kaplan-Meier survival curves of the prognostic value of LDH for CC were plotted for RNA-seq data. Functional enrichment analysis was performed for the genes co-expressed with LDH. Results: The data from our in-house clinical cases as well as the data extracted from microarrays and RNA-seq databases demonstrated significant overexpression of LDH in CC samples. Elevated LDH expression levels were associated with poor overall survival in CC patients. The genes co-expressed with LDH were significantly correlated with the biological processes and pathways, associated with nuclear division, the condensed chromosome, protein serine/threonine kinase activity, and the cell cycle. Conclusion: In conclusion, LDH upregulation might serve as a therapeutic and prognostic biomarker for CC.
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Affiliation(s)
- Yuping Ye
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Min Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xinyan Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jingyu Xiao
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lin Liao
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Faquan Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.,Address correspondence to: Faquan Lin, MD, Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Qingxiu District, Nanning 530021, Guangxi, China
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20
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Meixner E, Hoeltgen L, Hoegen P, König L, Arians N, Michel LL, Smetanay K, Fremd C, Schneeweiss A, Debus J, Hörner-Rieber J. Age-Dependent Hematologic Toxicity Profiles and Prognostic Serologic Markers in Postoperative Radiochemotherapy Treatment for Uterine Cervical Cancer. Technol Cancer Res Treat 2022; 21:15330338221118188. [PMID: 35950239 PMCID: PMC9379804 DOI: 10.1177/15330338221118188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Introduction: In the adjuvant setting for cervical cancer, classical
risk factors for postoperative radiochemotherapy have been established. However,
data on laboratory changes during therapy and the prognostic value of
serological markers are limited and further knowledge is needed to optimize the
toxic trimodal regimen. Methods: We retrospectively identified 69
women who underwent weekly postoperative radiochemotherapy with
40 mg/m2 of cisplatin for cervical cancer between 2010 and 2021
at a single center. Laboratory parameters were recorded before, at each cycle
and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to
calculate and compare survival, groups were compared using the Mann–Whitney
U, χ2, and variance tests. Results:
With a median follow-up of 17.7 months, the 1- and 5-year local control rates
were 94.0% and 73.7%, respectively, with significantly better rates for more
chemotherapy cycles and negative resection margins. Only 68.1% of patients
completed all cycles. The most common reasons for early discontinuation were
persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting
infections in women aged > 50 years. Leukopenia was more likely to occur
after the third cycle. Significantly worse survival was observed for
post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase
levels, low pre-radiochemotherapy nutritional index, and raised
C-reactive-protein-levels; the latter were also predictable for local control.
The Glasgow prognostic score did not reliably predict survival.
Conclusion: Incomplete application of simultaneous chemotherapy
leads to inferior local control, and age-dependent limiting factors should be
identified at an early stage. In addition to classical risk factors, serological
markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show
prognostic significance.
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Affiliation(s)
- Eva Meixner
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany
| | - Line Hoeltgen
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany
| | - Philipp Hoegen
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany
| | - Laila König
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany
| | - Nathalie Arians
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany
| | - Laura L Michel
- National Center for Tumor diseases (NCT), Heidelberg, Germany.,Department of Gynecology and Obstetrics, 9144Heidelberg University Hospital, Heidelberg, Germany
| | - Katharina Smetanay
- National Center for Tumor diseases (NCT), Heidelberg, Germany.,Department of Gynecology and Obstetrics, 9144Heidelberg University Hospital, Heidelberg, Germany
| | - Carlo Fremd
- National Center for Tumor diseases (NCT), Heidelberg, Germany.,Department of Gynecology and Obstetrics, 9144Heidelberg University Hospital, Heidelberg, Germany
| | - Andreas Schneeweiss
- National Center for Tumor diseases (NCT), Heidelberg, Germany.,Department of Gynecology and Obstetrics, 9144Heidelberg University Hospital, Heidelberg, Germany
| | - Jürgen Debus
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany.,Heidelberg Ion Therapy Center (HIT), Heidelberg, Germany.,Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Juliane Hörner-Rieber
- Department of Radiation Oncology, 27178Heidelberg University Hospital, Heidelberg, Germany.,Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,National Center for Tumor diseases (NCT), Heidelberg, Germany.,Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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21
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Li W, Cui X, Chen Z. Screening of lactate dehydrogenase inhibitor from bioactive compounds in natural products by electrophoretically mediated microanalysis. J Chromatogr A 2021; 1656:462554. [PMID: 34571279 DOI: 10.1016/j.chroma.2021.462554] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/26/2022]
Abstract
Lactate dehydrogenase (LDH) is a key enzyme in the glycolysis, which has been reported that the expression of LDH is elevated in a variety of cancer types and can promote tumor invasion and metastasis. Therefore, LDH has come to be an emerging therapeutic target for cancer. In this work, we described a new strategy for rapid screening of LDH inhibitors from natural products by integrating electrophoretically mediated microanalysis (EMMA), transverse diffusion of laminar flow profiles (TDLFP) and rapid pressure direction switching. LDH activity could be assayed by the quantification of the peak area of the produced β-Nicotinamide adenine dinucleotide hydrate (NAD+) and the inhibitory effect on LDH was reflected by the reduction of NAD+ peak area. Parameters affecting CE separation and enzymatic reaction were evaluated, including the pH of background electrolyte, incubation time, methanol percentage and enzyme concentration. The Michaelis-Menten constant (Km) determined on-line by EMMA method were 226.9 μM and 31.8 μM for substrates sodium pyruvate and NADH, respectively and the half-maximal inhibitory concentration (IC50) for the known positive inhibitor gossypol was determined to be 9.269 μM, which was comparable with the previous literature. Then the inhibitory activity of 12 bioactive compounds from natural products on LDH was investigated by employing the developed method. Three compounds including quercetin, luteolin, ursolic acid had potential inhibitory effect on LDH. Molecular docking study was implemented and well supported the experimental results. This study provides a potential tool for the preliminary screening of LDH inhibitors from bioactive compounds in natural products by capillary electrophoresis.
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Affiliation(s)
- Wen Li
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China; State Key Laboratory of Transducer Technology, Chinese Academy of Sciences, Beijing 10080, China
| | - Xinyue Cui
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China
| | - Zilin Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China; State Key Laboratory of Transducer Technology, Chinese Academy of Sciences, Beijing 10080, China.
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22
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Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH. Biomedicines 2021; 9:biomedicines9111526. [PMID: 34829755 PMCID: PMC8615101 DOI: 10.3390/biomedicines9111526] [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: 08/16/2021] [Revised: 10/13/2021] [Accepted: 10/22/2021] [Indexed: 12/20/2022] Open
Abstract
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
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Jain A, Bhardwaj V. Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities. World J Gastroenterol 2021; 27:6527-6550. [PMID: 34754151 PMCID: PMC8554400 DOI: 10.3748/wjg.v27.i39.6527] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/22/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Although chemotherapeutic regimens such as gemcitabine+ nab-paclitaxel and FOLFIRINOX (FOLinic acid, 5-Fluroruracil, IRINotecan, and Oxaliplatin) significantly improve patient survival, the prevalence of therapy resistance remains a major roadblock in the success of these agents. This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy. Specifically, we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms. Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor's immunological response.
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Affiliation(s)
- Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Vikas Bhardwaj
- Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, United States
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24
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Gao Y, Wei L, Kim SJ, Wang L, He Y, Zheng Y, Bertero L, Pellerino A, Cassoni P, Tamagnone L, Theresa PK, Deutsch A, Zhan H, Lai J, Wang Y, You H. A Novel Prognostic Marker for Primary CNS Lymphoma: Lactate Dehydrogenase-to-Lymphocyte Ratio Improves Stratification of Patients Within the Low and Intermediate MSKCC Risk Groups. Front Oncol 2021; 11:696147. [PMID: 34422649 PMCID: PMC8370855 DOI: 10.3389/fonc.2021.696147] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/05/2021] [Indexed: 12/23/2022] Open
Abstract
Background Primary central nervous system lymphoma (PCNSL) is a highly aggressive and rare extranodal non-Hodgkin lymphoma (NHL). The MSKCC and the IELSG scores represent the most widely used prognostic models, but many changes have occurred in therapeutic protocols since their development. Moreover, many PCNSL patients cannot be classified using the IELSG score. We thus aimed to create a novel, effective and feasible prognostic model for PCNSL. Methods We included 248 PCNSL patients diagnosed with PCNSL. Our primary endpoint was the overall survival (OS) and we used the receiver operating characteristic (ROC) analysis to determine the optimal prognostic cut-off value for LLR (lactate dehydrogenase-to-lymphocyte ratio), neutrophil-to-lymphocyte ratio (NLR) and derived neutrophil-to-lymphocyte ratio (dNLR). Variable associated with OS were evaluated by univariate and multivariate analyses. 124 out of 248 patients were randomly selected as the internal validation cohort. Results By univariate analysis, an age >60 years, Eastern Cooperative Oncology Group performance status (ECOG PS) >1, treatment with radiotherapy alone, high-risk groups of Memorial Sloan Kettering Cancer Center (MSKCC) score, NLR >4.74, dNLR >3.29, and LLR >166.8 were significantly associated with a worse OS. By multivariate analysis, the MSKCC score and LLR were confirmed as independent prognostic parameters for poorer OS. OS, however, was not significantly different between low- and intermediate-risk groups according to the MSKCC score, while LLR proved to be prognostically relevant and was thus used to develop a novel, effective three-tier PCNSL scoring system. Of 124 patients, 84 patients with survival data and LLR data were successfully validated by newly established PCNSL LLR scoring system. Conclusions In the present study, we demonstrate that a high LLR represents an independent unfavorable prognostic parameter in PCNSL patients which can be integrated into an effective prognostic model.
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Affiliation(s)
- Yuting Gao
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Li Wei
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.,NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China
| | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Liang Wang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yingzhi He
- Department of Hematology, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
| | - Yanfang Zheng
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.,Department of Oncology, ZhuJiang Hospital of Southern Medical University, Guangzhou, China
| | - Luca Bertero
- Pathology Unit, Department of Medical Sciences, University of Turin, Torino, Italy
| | - Alessia Pellerino
- Department of Neuro-Oncology, University and City of Health and Science Hospital, Torino, Italy
| | - Paola Cassoni
- Pathology Unit, Department of Medical Sciences, University of Turin, Torino, Italy
| | - Luca Tamagnone
- Università Cattolica del Sacro Cuore, Department of Life Sciences and Public Health, Rome, Italy.,Fondazione Policlinico Universitario "A. Gemelli"- IRCCS, Rome, Italy
| | | | - Alexander Deutsch
- Clinical Department of Hematology, Medical University of Graz, Graz, Austria
| | - Huien Zhan
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jing Lai
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yao Wang
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Hua You
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
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25
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Miro C, Nappi A, Cicatiello AG, Di Cicco E, Sagliocchi S, Murolo M, Belli V, Troiani T, Albanese S, Amiranda S, Zavacki AM, Stornaiuolo M, Mancini M, Salvatore D, Dentice M. Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas. Cancers (Basel) 2021; 13:cancers13112743. [PMID: 34205977 PMCID: PMC8199095 DOI: 10.3390/cancers13112743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 01/12/2023] Open
Abstract
Simple Summary Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. Aerobic glycolysis is a prominent trait of many cancers; contextually, glutamine addiction, enhanced glucose uptake and aerobic glycolysis sustain the metabolic needs of rapidly proliferating cancer cells. Thyroid hormone (TH) is a positive regulator of tumor progression and metastatic conversion of squamous cell carcinoma (SCC). Accordingly, overexpression of the TH activating enzyme, D2, is associated with metastatic SCC. The aim of our study was to assess the ability of TH and its activating enzyme in promoting key tracts of cancer progression such as angiogenesis, response to hypoxia and metabolic adaptation. By performing in vivo and in vitro studies, we demonstrate that TH induces VEGF-A in cancer cells and fosters aerobic glycolysis inducing pro-glycolytic mediators, thus implying that TH signal attenuation represents a therapeutic tool to contrast tumor angiogenesis and tumor progression. Abstract Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the VEGF-A gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a TH–VEGF-A–HIF1α regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.
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Affiliation(s)
- Caterina Miro
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Annarita Nappi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Annunziata Gaetana Cicatiello
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Emery Di Cicco
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Serena Sagliocchi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Melania Murolo
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
| | - Valentina Belli
- Laboratorio di Oncologia Molecolare, Dipartimento di Medicina di Precisione, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy; (V.B.); (T.T.)
| | - Teresa Troiani
- Laboratorio di Oncologia Molecolare, Dipartimento di Medicina di Precisione, University of Campania Luigi Vanvitelli, 81100 Caserta, Italy; (V.B.); (T.T.)
| | - Sandra Albanese
- Institute of Biostructures and Bioimaging of the National Research Council, 80131 Naples, Italy; (S.A.); (M.M.)
| | - Sara Amiranda
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy;
- CEINGE–Biotecnologie Avanzate Scarl, 80131 Naples, Italy;
| | - Ann Marie Zavacki
- Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 01451, USA;
| | - Mariano Stornaiuolo
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy;
| | - Marcello Mancini
- Institute of Biostructures and Bioimaging of the National Research Council, 80131 Naples, Italy; (S.A.); (M.M.)
| | - Domenico Salvatore
- CEINGE–Biotecnologie Avanzate Scarl, 80131 Naples, Italy;
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (C.M.); (A.N.); (A.G.C.); (E.D.C.); (S.S.); (M.M.)
- CEINGE–Biotecnologie Avanzate Scarl, 80131 Naples, Italy;
- Correspondence:
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26
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Vallée A, Lecarpentier Y, Vallée JN. Opposed Interplay between IDH1 Mutations and the WNT/β-Catenin Pathway: Added Information for Glioma Classification. Biomedicines 2021; 9:biomedicines9060619. [PMID: 34070746 PMCID: PMC8229353 DOI: 10.3390/biomedicines9060619] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/23/2022] Open
Abstract
Gliomas are the main common primary intraparenchymal brain tumor in the central nervous system (CNS), with approximately 7% of the death caused by cancers. In the WHO 2016 classification, molecular dysregulations are part of the definition of particular brain tumor entities for the first time. Nevertheless, the underlying molecular mechanisms remain unclear. Several studies have shown that 75% to 80% of secondary glioblastoma (GBM) showed IDH1 mutations, whereas only 5% of primary GBM have IDH1 mutations. IDH1 mutations lead to better overall survival in gliomas patients. IDH1 mutations are associated with lower stimulation of the HIF-1α a, aerobic glycolysis and angiogenesis. The stimulation of HIF-1α and the process of angiogenesis appears to be activated only when hypoxia occurs in IDH1-mutated gliomas. In contrast, the observed upregulation of the canonical WNT/β-catenin pathway in gliomas is associated with proliferation, invasion, aggressive-ness and angiogenesis.. Molecular pathways of the malignancy process are involved in early stages of WNT/β-catenin pathway-activated-gliomas, and this even under normoxic conditions. IDH1 mutations lead to decreased activity of the WNT/β-catenin pathway and its enzymatic targets. The opposed interplay between IDH1 mutations and the canonical WNT/β-catenin pathway in gliomas could participate in better understanding of the observed evolution of different tumors and could reinforce the glioma classification.
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Affiliation(s)
- Alexandre Vallée
- Department of Clinical Research and Innovation, Foch Hospital, 92150 Suresnes, France
- Correspondence:
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l’Est Francilien (GHEF), 77100 Meaux, France;
| | - Jean-Noël Vallée
- Centre Hospitalier Universitaire (CHU) Amiens Picardie, Université Picardie Jules Verne (UPJV), 80000 Amiens, France;
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 86000 Poitiers, France
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Vallée A, Lecarpentier Y, Vallée R, Guillevin R, Vallée JN. Circadian Rhythms in Exudative Age-Related Macular Degeneration: The Key Role of the Canonical WNT/β-Catenin Pathway. Int J Mol Sci 2020; 21:ijms21030820. [PMID: 32012797 PMCID: PMC7037737 DOI: 10.3390/ijms21030820] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/23/2020] [Accepted: 01/27/2020] [Indexed: 02/07/2023] Open
Abstract
Age-related macular degeneration (AMD) is considered as the main worldwide cause of blindness in elderly adults. Exudative AMD type represents 10 to 15% of macular degeneration cases, but is the main cause of vision loss and blindness. Circadian rhythm changes are associated with aging and could further accelerate it. However, the link between circadian rhythms and exudative AMD is not fully understood. Some evidence suggests that dysregulation of circadian functions could be manifestations of diseases or could be risk factors for the development of disease in elderly adults. Biological rhythms are complex systems interacting with the environment and control several physiological pathways. Recent findings have shown that the dysregulation of circadian rhythms is correlated with exudative AMD. One of the main pathways involved in exudative AMD is the canonical WNT/β-catenin pathway. Circadian clocks have a main role in some tissues by driving the circadian expression of genes involved in physiological and metabolic functions. In exudative AMD, the increase of the canonical WNT/β-catenin pathway is enhanced by the dysregulation of circadian rhythms. Exudative AMD progression is associated with major metabolic reprogramming, initiated by aberrant WNT/β-catenin pathway, of aerobic glycolysis. This review focuses on the interest of circadian rhythm dysregulation in exudative AMD through the aberrant upregulation of the canonical WNT/β-catenin pathway.
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Affiliation(s)
- Alexandre Vallée
- DACTIM-MIS, Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, CHU de Poitiers, 86021 Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), 77100 Meaux, France
| | - Rodolphe Vallée
- University Hospital Group of Paris-Seine-Saint-Denis, APHP, University of Paris-13 Sorbonne Paris-Cité, 93000 Paris, France
| | - Rémy Guillevin
- DACTIM-MIS, Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, CHU de Poitiers, 86021 Poitiers, France
| | - Jean-Noël Vallée
- CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), 80000 Amiens, France
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, 86021 Poitiers, France
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Thomas R, Shaath H, Naik A, Toor SM, Elkord E, Decock J. Identification of two HLA-A*0201 immunogenic epitopes of lactate dehydrogenase C (LDHC): potential novel targets for cancer immunotherapy. Cancer Immunol Immunother 2020; 69:449-463. [PMID: 31932876 PMCID: PMC7044258 DOI: 10.1007/s00262-020-02480-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 01/04/2020] [Indexed: 12/13/2022]
Abstract
Lactate dehydrogenase C (LDHC) is an archetypical cancer testis antigen with limited expression in adult tissues and re-expression in tumors. This restricted expression pattern together with the important role of LDHC in cancer metabolism renders LDHC a potential target for immunotherapy. This study is the first to investigate the immunogenicity of LDHC using T cells from healthy individuals. LDHC-specific T cell responses were induced by in vitro stimulation with synthetic peptides, or by priming with autologous peptide-pulsed dendritic cells. We evaluated T cell activation by IFN-γ ELISpot and determined cytolytic activity of HLA-A*0201-restricted T cells in breast cancer cell co-cultures. In vitro T cell stimulation induced IFN-γ secretion in response to numerous LDHC-derived peptides. Analysis of HLA-A*0201 responses revealed a significant T cell activation after stimulation with peptide pools 2 (PP2) and 8 (PP8). The PP2- and PP8-specific T cells displayed cytolytic activity against breast cancer cells with endogenous LDHC expression within a HLA-A*0201 context. We identified peptides LDHC41−55 and LDHC288−303 from PP2 and PP8 to elicit a functional cellular immune response. More specifically, we found an increase in IFN-γ secretion by CD8 + T cells and cancer-cell-killing of HLA-A*0201/LDHC positive breast cancer cells by LDHC41−55- and LDHC288−303-induced T cells, albeit with a possible antigen recognition threshold. The majority of induced T cells displayed an effector memory phenotype. To conclude, our findings support the rationale to assess LDHC as a targetable cancer testis antigen for immunotherapy, and in particular the HLA-A*0201 restricted LDHC41–55 and LDHC288–303 peptides within LDHC.
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Affiliation(s)
- Remy Thomas
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Hibah Shaath
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Adviti Naik
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Salman M Toor
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Eyad Elkord
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Julie Decock
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
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Wang ZH, Zhang YZ, Wang YS, Ma XX. Identification of novel cell glycolysis related gene signature predicting survival in patients with endometrial cancer. Cancer Cell Int 2019; 19:296. [PMID: 31807118 PMCID: PMC6857303 DOI: 10.1186/s12935-019-1001-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 10/24/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Endometrial cancer (EC) is one of the three major gynecological malignancies. Numerous biomarkers that may be associated with survival and prognosis have been identified through database mining in previous studies. However, the predictive ability of single-gene biomarkers is not sufficiently specific. Genetic signatures may be an improved option for prediction. This study aimed to explore data from The Cancer Genome Atlas (TCGA) to identify a new genetic signature for predicting the prognosis of EC. METHODS mRNA expression profiling was performed in a group of patients with EC (n = 548) from TCGA. Gene set enrichment analysis was performed to identify gene sets that were significantly different between EC tissues and normal tissues. Cox proportional hazards regression models were used to identify genes significantly associated with overall survival. Quantitative real-time-PCR was used to verify the reliability of the expression of selected mRNAs. Subsequent multivariate Cox regression analysis was used to establish a prognostic risk parameter formula. Kaplan-Meier survival estimates and the log-rank test were used to validate the significance of risk parameters for prognosis prediction. RESULT Nine genes associated with glycolysis (CLDN9, B4GALT1, GMPPB, B4GALT4, AK4, CHST6, PC, GPC1, and SRD5A3) were found to be significantly related to overall survival. The results of mRNA expression analysis by PCR were consistent with those of bioinformatics analysis. Based on the nine-gene signature, the 548 patients with EC were divided into high/low-risk subgroups. The prognostic ability of the nine-gene signature was not affected by other factors. CONCLUSION A nine-gene signature associated with cellular glycolysis for predicting the survival of patients with EC was developed. The findings provide insight into the mechanisms of cellular glycolysis and identification of patients with poor prognosis in EC.
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Affiliation(s)
- Zi-Hao Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110021 People’s Republic of China
| | - Yun-Zheng Zhang
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110021 People’s Republic of China
| | - Yu-Shan Wang
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110021 People’s Republic of China
| | - Xiao-Xin Ma
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110021 People’s Republic of China
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Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment. Cancers (Basel) 2019; 11:cancers11060750. [PMID: 31146503 PMCID: PMC6627402 DOI: 10.3390/cancers11060750] [Citation(s) in RCA: 194] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 02/07/2023] Open
Abstract
Cancer is a metabolic disease in which abnormally proliferating cancer cells rewire metabolic pathways in the tumor microenvironment (TME). Molecular reprogramming in the TME helps cancer cells to fulfill elevated metabolic demands for bioenergetics and cellular biosynthesis. One of the ways through which cancer cell achieve this is by regulating the expression of metabolic enzymes. Lactate dehydrogenase (LDH) is the primary metabolic enzyme that converts pyruvate to lactate and vice versa. LDH also plays a significant role in regulating nutrient exchange between tumor and stroma. Thus, targeting human lactate dehydrogenase for treating advanced carcinomas may be of benefit. LDHA and LDHB, two isoenzymes of LDH, participate in tumor stroma metabolic interaction and exchange of metabolic fuel and thus could serve as potential anticancer drug targets. This article reviews recent research discussing the roles of lactate dehydrogenase in cancer metabolism. As molecular regulation of LDHA and LDHB in different cancer remains obscure, we also review signaling pathways regulating LDHA and LDHB expression. We highlight on the role of small molecule inhibitors in targeting LDH activity and we emphasize the development of safer and more effective LDH inhibitors. We trust that this review will also generate interest in designing combination therapies based on LDH inhibition, with LDHA being targeted in tumors and LDHB in stromal cells for better treatment outcome.
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Tumor Identification of Less Aggressive or Indolent Lymphoma With Whole-Body 11C-Acetate PET/CT. Clin Nucl Med 2019; 44:276-281. [PMID: 30688736 DOI: 10.1097/rlu.0000000000002464] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE The aim of this study was to investigate the diagnostic performance of whole-body [C]acetate PET/CT in less aggressive or indolent lymphomas, wherein [F]FDG PET/CT would exhibit limited sensitivity. METHODS Between September 2016 and May 2018, we prospectively evaluated 17 patients (9 men, 8 women; mean age [range], 71 [45-87] years) with pathologically proven less aggressive or indolent lymphomas according to Non-Hodgkin's Lymphoma Classification Project, using both [F]FDG PET/CT and [C]acetate PET/CT (performed on the same day). Detected nodal lesions were recorded according to the Ann Arbor classification. Extranodal (EN) lesions were also evaluated. We compared whole-body lesion detection between [F] FDG PET/CT and [C]acetate PET/CT using the McNemar test. RESULTS In all patients, significantly more nodal and EN lesions were detected using [C]acetate PET/CT than [F]FDG PET/CT (nodal: 84 vs 64 regions; P < 0.001; EN: 26 vs 19 regions, P = 0.039). Bone lesions were detected in 8 and 5 patients using [C]acetate PET/CT and [F]FDG PET/CT, respectively (P = 0.25). Among the 14 patients (82.4%) who underwent bone marrow biopsy, bone marrow involvement was detected with sensitivities of 100% (6/6 patients) and 80% (5/6 patients) using [C]acetate PET/CT and [F]FDG PET/CT, respectively. Multiple areas of focal uptake in the spleen of 1 patient were exhibited on [F]FDG PET/CT but not [C]acetate PET/CT. CONCLUSIONS [C]acetate PET/CT exhibited greater sensitivity than [F]FDG PET/CT for lesion detection in patients with less aggressive or indolent lymphomas, thus promising applicability as a physiological tracer in the study of such lesions.
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Yu M, Chen S, Hong W, Gu Y, Huang B, Lin Y, Zhou Y, Jin H, Deng Y, Tu L, Hou B, Jian Z. Prognostic role of glycolysis for cancer outcome: evidence from 86 studies. J Cancer Res Clin Oncol 2019; 145:967-999. [PMID: 30825027 DOI: 10.1007/s00432-019-02847-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 01/14/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The abnormal expression of the key enzymes in glycolytic pathways, including glucose transporter-1, glucose transporter-3, hexokinase-II, lactate dehydrogenase 5, pyruvate kinase M2, glucose-6-phosphate dehydrogenase, transketolase-like protein 1 and pyruvate dehydrogenase kinase-1 was reported to be associated with poor prognosis of various cancers. However, the association remains controversial. The objective of this study was to investigate the prognostic significance of glycolysis-related proteins. MATERIALS AND METHODS We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, using Pubmed and Ovid as search engines and Google Scholar from inception to April 2017. Eighty-six studies with 12,002 patients were included in the study. RESULTS Our pooled results identified that glycolysis-related proteins in cancers were associated with shorter overall survival of colorectal cancer (HR 2.33, 95% CI 1.38-3.93, P = 0.002), gastric cancer (HR 1.55, 95% CI 1.31-1.82, P < 0.001), cancer of gallbladder or bile duct (HR 2.16, 95% CI 1.70-2.75, P < 0.001), oral cancer (HR 2.07, 95% CI 1.32-3.25, P < 0.001), esophageal cancer (HR 1.66, 95% CI 1.25-2.21, P = 0.01), hepatocellular carcinoma (HR 2.04, 95% CI 1.64-2.54, P < 0.001), pancreatic cancer (HR 1.72, 95% CI 1.39-2.13, P < 0.001), breast cancer(HR 1.67, 95% CI 1.34-2.08, P < 0.001), and nasopharyngeal carcinoma (HR 3.59, 95% CI 1.75-7.36, P < 0.001). No association was found for lung cancer, ovarian cancer or melanoma. The key glycolytic transcriptional regulators (HIF-1α, p53) were analyzed in parallel to the glycolysis-related proteins, and the pooled results identified that high-level expression of HIF-1α was significantly associated with shorter overall survival (HR 0.57, 95% CI 0.42-0.79, P < 0.001) Furthermore, glycolysis-related proteins linked with poor differentiated tumors (OR 1.81, 95% CI 1.46-2.25, P < 0.001), positive lymph node metastasis (OR 2.73, 95% CI 2.16-3.46, P < 0.001), positive vascular invasion (OR 2.05, 95% CI 1.37-3.07, P < 0.001), large tumor size (OR 2.06, 95% CI 1.80-2.37, P < 0.001), advanced tumor stage (OR 1.58, 95% CI 1.19-2.09, P < 0.001), and deeper invasion (OR 2.37, 95% CI 1.93-2.91, P < 0.001). CONCLUSION Glycolytic transcriptional regulators and glycolysis-related proteins in cancers were significantly associated with poor prognosis, suggesting glycolytic status may be potentially valuable prognostic biomarkers for various cancers.
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Affiliation(s)
- Min Yu
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
| | - Shengying Chen
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Weifeng Hong
- The Second Clinical Medical College, Guangzhou Medical University, Guangzhou, China
| | - Yujun Gu
- The Second Clinical Medical College, Guangzhou Medical University, Guangzhou, China
| | - Bowen Huang
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Ye Lin
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yu Zhou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Haosheng Jin
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yanying Deng
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Lei Tu
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
| | - Zhixiang Jian
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
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Alves A, Mamede A, Alves M, Oliveira P, Rocha S, Botelho M, Maia C. Glycolysis Inhibition as a Strategy for Hepatocellular Carcinoma Treatment? Curr Cancer Drug Targets 2018; 19:26-40. [DOI: 10.2174/1568009618666180430144441] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 03/05/2018] [Accepted: 03/10/2018] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most frequently detected primary malignant liver tumor, representing a worldwide public health problem due to its high morbidity and mortality rates. The HCC is commonly detected in advanced stage, precluding the use of treatments with curative intent. For this reason, it is crucial to find effective therapies for HCC. Cancer cells have a high dependence of glycolysis for ATP production, especially under hypoxic environment. Such dependence provides a reliable possible strategy to specifically target cancer cells based on the inhibition of glycolysis. HCC, such as other cancer types, presents a clinically well-known upregulation of several glycolytic key enzymes and proteins, including glucose transporters particularly glucose transporter 1 (GLUT1). Such enzymes and proteins constitute potential targets for therapy. Indeed, for some of these targets, several inhibitors were already reported, such as 2-Deoxyglucose, Imatinib or Flavonoids. Although the inhibition of glycolysis presents a great potential for an anticancer therapy, the development of glycolytic inhibitors as a new class of anticancer agents needs to be more explored. Herein, we propose to summarize, discuss and present an overview on the different approaches to inhibit the glycolytic metabolism in cancer cells, which may be very effective in the treatment of HCC.
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Affiliation(s)
- A.P. Alves
- Centro de Investigacao em Ciencias da Saude (CICS-UBI), Universidade da Beira Interior, Covilha, Portugal
| | - A.C. Mamede
- Centro de Investigacao em Ciencias da Saude (CICS-UBI), Universidade da Beira Interior, Covilha, Portugal
| | - M.G. Alves
- Centro de Investigacao em Ciencias da Saude (CICS-UBI), Universidade da Beira Interior, Covilha, Portugal
| | - P.F. Oliveira
- Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) and Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Porto, Portugal
| | - S.M. Rocha
- Centro de Investigacao em Ciencias da Saude (CICS-UBI), Universidade da Beira Interior, Covilha, Portugal
| | - M.F. Botelho
- Biophysics Unit, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - C.J. Maia
- Centro de Investigacao em Ciencias da Saude (CICS-UBI), Universidade da Beira Interior, Covilha, Portugal
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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: 426] [Impact Index Per Article: 60.9] [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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Vallée A, Guillevin R, Vallée JN. Vasculogenesis and angiogenesis initiation under normoxic conditions through Wnt/β-catenin pathway in gliomas. Rev Neurosci 2018; 29:71-91. [PMID: 28822229 DOI: 10.1515/revneuro-2017-0032] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 06/25/2017] [Indexed: 12/11/2022]
Abstract
The canonical Wnt/β-catenin pathway is up-regulated in gliomas and involved in proliferation, invasion, apoptosis, vasculogenesis and angiogenesis. Nuclear β-catenin accumulation correlates with malignancy. Hypoxia activates hypoxia-inducible factor (HIF)-1α by inhibiting HIF-1α prolyl hydroxylation, which promotes glycolytic energy metabolism, vasculogenesis and angiogenesis, whereas HIF-1α is degraded by the HIF prolyl hydroxylase under normoxic conditions. We focus this review on the links between the activated Wnt/β-catenin pathway and the mechanisms underlying vasculogenesis and angiogenesis through HIF-1α under normoxic conditions in gliomas. Wnt-induced epidermal growth factor receptor/phosphatidylinositol 3-kinase (PI3K)/Akt signaling, Wnt-induced signal transducers and activators of transcription 3 (STAT3) signaling, and Wnt/β-catenin target gene transduction (c-Myc) can activate HIF-1α in a hypoxia-independent manner. The PI3K/Akt/mammalian target of rapamycin pathway activates HIF-1α through eukaryotic translation initiation factor 4E-binding protein 1 and STAT3. The β-catenin/T-cell factor 4 complex directly binds to STAT3 and activates HIF-1α, which up-regulates the Wnt/β-catenin target genes cyclin D1 and c-Myc in a positive feedback loop. Phosphorylated STAT3 by interleukin-6 or leukemia inhibitory factor activates HIF-1α even under normoxic conditions. The activation of the Wnt/β-catenin pathway induces, via the Wnt target genes c-Myc and cyclin D1 or via HIF-1α, gene transactivation encoding aerobic glycolysis enzymes, such as glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production, as the primary alternative of ATP, at all oxygen levels, even in normoxic conditions. Lactate released by glioma cells via the monocarboxylate lactate transporter-1 up-regulated by HIF-1α and lactate anion activates HIF-1α in normoxic endothelial cells by inhibiting HIF-1α prolyl hydroxylation and preventing HIF labeling by the von Hippel-Lindau protein. Increased lactate with acid environment and HIF-1α overexpression induce the vascular endothelial growth factor (VEGF) pathway of vasculogenesis and angiogenesis under normoxic conditions. Hypoxia and acidic pH have no synergistic effect on VEGF transcription.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, 11 Boulevard Marie et Pierre Curie, F-86000 Poitiers, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, Université de Poitiers et CHU de Poitiers, F-86000 Poitiers, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, University of Poitiers, F-86000 Poitiers, France
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Zhang SL, He Y, Tam KY. Targeting cancer metabolism to develop human lactate dehydrogenase ( h LDH)5 inhibitors. Drug Discov Today 2018; 23:1407-1415. [DOI: 10.1016/j.drudis.2018.05.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 03/14/2018] [Accepted: 05/02/2018] [Indexed: 12/15/2022]
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Cao W, Fang L, Teng S, Chen H, Wang Z. Computer-aided discovery and biological characterization of human lactate dehydrogenase 5 inhibitors with anti-osteosarcoma activity. Bioorg Med Chem Lett 2018; 28:2229-2233. [PMID: 29861142 DOI: 10.1016/j.bmcl.2018.05.052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 02/07/2023]
Abstract
Human lactate dehydrogenase 5 (hLDH5) is overexpressed in various tissues of human tumors, which could be a potential therapeutic target for cancer treatment. Herein, we describe the computer-aided discovery and biological characterizations of hLDH5 inhibitors with anti-osteosarcoma activity. Biochemical assay indicated that the identified compounds 3 and 9 strongly inhibited hLDH5 function with EC50 values of 0.67 and 0.39 µM, respectively. The MTT assay revealed that most of the identified inhibitors had little effect on MG-63 cell proliferation at 4 µM, only 9 reduced the cancer cell proliferation at the same concentration, with an IC50 value of 3.18 µM. Our data suggested that 9 could be a starting lead of developing potent hLDH5 inhibitor for the anti-osteosarcoma agents in cancer treatment.
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Affiliation(s)
- Wei Cao
- Clinical Laboratory of Beijing Rehabilitation Hospital of Capital Medical University, Xixia Zhuang, Bada Chu, Shijingshan District, Beijing, China
| | - Le Fang
- Department of Blood Transfusion, 521 Hospital of Ordnance Industry, Xi'an, China
| | - Siyong Teng
- National Center for Cardiovascular Diseases, No. 167 North Lishi Road, Xicheng District, Beijing, China
| | - Hongwei Chen
- Shanghai Songjiang District Central Hospital, Yuanzhong Road, Songjiang District, Shanghai, China
| | - Zhan Wang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China.
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A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial. Cancer Chemother Pharmacol 2018; 81:829-838. [DOI: 10.1007/s00280-018-3556-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/28/2018] [Indexed: 12/12/2022]
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39
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Oei RW, Ye L, Kong F, Du C, Zhai R, Xu T, Shen C, Wang X, He X, Kong L, Hu C, Ying H. Pre-treatment Serum Lactate Dehydrogenase is Predictive of Survival in Patients with Nasopharyngeal Carcinoma Undergoing Intensity-Modulated Radiotherapy. J Cancer 2018; 9:54-63. [PMID: 29290769 PMCID: PMC5743711 DOI: 10.7150/jca.22190] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/24/2017] [Indexed: 12/16/2022] Open
Abstract
Objective:To analyze the prognostic value of pre-treatment serum lactate dehydrogenase (SLDH) level in patients with nasopharyngeal carcinoma (NPC) receiving intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Methods:From January 2010 to March 2013, 427 eligible patients were reviewed. Pre-treatment SLDH level was measured within 2 weeks prior to treatment. Receiver operating characteristic (ROC) curve analysis was performed to select the optimal cutoff point. The impact of pre-treatment SLDH on overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. Further propensity score matching was carried out to adjust bias. Results:The optimal cutoff point of 168.5 IU/L was selected based on ROC curve analysis. Multivariate analysis showed that high pre-treatment SLDH level was an independent prognostic factor for OS (P=0.001), PFS (P=0.004) and DMFS (P=0.001). After propensity score matching was performed, it remained to be significantly associated with poor OS (P=0.009), PFS (P=0.015) and DMFS (P=0.008) in the adjusted model. Conclusion:High pre-treatment SLDH level predicts poor survival in patients with NPC treated with IMRT-based therapy. As a routinely performed biomarker, pre-treatment SLDH can be utilized in combination with current Tumor-Node-Metastasis staging to predict survival and to plan a personalized treatment in these patients.
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Affiliation(s)
- Ronald Wihal Oei
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Lulu Ye
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Fangfang Kong
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Chengrun Du
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Ruiping Zhai
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Tingting Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Chunying Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Xiaoshen Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Xiayun He
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Lin Kong
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Chaosu Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
| | - Hongmei Ying
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, P.R China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P.R China
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Rai G, Brimacombe KR, Mott BT, Urban DJ, Hu X, Yang SM, Lee TD, Cheff DM, Kouznetsova J, Benavides GA, Pohida K, Kuenstner EJ, Luci DK, Lukacs CM, Davies DR, Dranow DM, Zhu H, Sulikowski G, Moore WJ, Stott GM, Flint AJ, Hall MD, Darley-Usmar VM, Neckers LM, Dang CV, Waterson AG, Simeonov A, Jadhav A, Maloney DJ. Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). J Med Chem 2017; 60:9184-9204. [PMID: 29120638 PMCID: PMC5894102 DOI: 10.1021/acs.jmedchem.7b00941] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.
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Affiliation(s)
- Ganesha Rai
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Kyle R. Brimacombe
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Bryan T. Mott
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Daniel J. Urban
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Xin Hu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Shyh-Ming Yang
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Tobie D. Lee
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Dorian M. Cheff
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Jennifer Kouznetsova
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Gloria A. Benavides
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
| | - Katie Pohida
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Eric J. Kuenstner
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Diane K. Luci
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | | | - Douglas R. Davies
- Beryllium Discovery Corp, 7869 Day Rd West, Bainbridge Island, WA, 98110
| | - David M. Dranow
- Beryllium Discovery Corp, 7869 Day Rd West, Bainbridge Island, WA, 98110
| | - Hu Zhu
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Gary Sulikowski
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, 37232
| | - William J. Moore
- NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702
| | - Gordon M. Stott
- NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702
| | - Andrew J. Flint
- NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702
| | - Matthew D. Hall
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Victor M. Darley-Usmar
- Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
| | - Leonard M. Neckers
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland, 20892
| | - Chi V. Dang
- Abramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadephia, Pennsylvania, 19104
| | - Alex G. Waterson
- Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, 37232
| | - Anton Simeonov
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - Ajit Jadhav
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
| | - David J. Maloney
- National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland, 20850
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Wang H, Zhou R, Sun L, Xia J, Yang X, Pan C, Huang N, Shi M, Bin J, Liao Y, Liao W. TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis. Endocr Relat Cancer 2017; 24:565-578. [PMID: 28874393 PMCID: PMC5633043 DOI: 10.1530/erc-17-0058] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 09/04/2017] [Indexed: 01/03/2023]
Abstract
Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.
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Affiliation(s)
- Hongqiang Wang
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
- Department of OncologyZhoushan Hospital, Zhoushan, China
| | - Rui Zhou
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Sun
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianling Xia
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuchun Yang
- Department of OncologyZhoushan Hospital, Zhoushan, China
| | - Changqie Pan
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Na Huang
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Min Shi
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianping Bin
- Department of CardiologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yulin Liao
- Department of CardiologyNanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wangjun Liao
- Department of OncologyNanfang Hospital, Southern Medical University, Guangzhou, China
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. PPARγ agonists: Potential treatments for exudative age-related macular degeneration. Life Sci 2017; 188:123-130. [PMID: 28887057 DOI: 10.1016/j.lfs.2017.09.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/29/2017] [Accepted: 09/05/2017] [Indexed: 12/22/2022]
Abstract
Choroidal neovascularization (CNV) characterizes the progression of exudative age-related macular degeneration (AMD) with the deterioration in the central vision. Vascular inflammation, and overproduction of inflammatory cytokines, growth factors and aberrant endothelial cell migration, initiate defective blood vessel proliferation in exudative AMD. CNV formation is initiated by the interplay between inflammation, the hallmark of exudative AMD, and the activation of WNT/β-catenin pathway. Upregulation of WNT/β-catenin pathway involves activation of PI3K/Akt pathway and then the Warburg effect to produce lactate. Lactate production generates VEGF expression and then participates to the initiation of CNV in exudative AMD. WNT/β-catenin pathway and PPARγ act in an opposite manner in several diseases. We focus this review on the interplay between PPARγ and canonical WNT/β-catenin pathway and the anti-inflammatory role of PPARγ in exudative AMD. In exudative AMD, PPARγ agonists downregulate inflammation and the WNT/β-catenin pathway. PPARγ agonists can appear as promising treatment against the initiation and the progression of CNV in exudative AMD.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France; Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, France.
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Rémy Guillevin
- Université de Poitiers et CHU de Poitiers, DACTIM, Laboratoire de Mathématiques et Applications, UMR CNRS 7348, SP2MI, Futuroscope, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, France; CHU Amiens Picardie, Université Picardie Jules Verne (UPJV), Amiens, France
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Aerobic Glycolysis Hypothesis Through WNT/Beta-Catenin Pathway in Exudative Age-Related Macular Degeneration. J Mol Neurosci 2017; 62:368-379. [PMID: 28689265 DOI: 10.1007/s12031-017-0947-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 06/28/2017] [Indexed: 12/18/2022]
Abstract
Exudative age-related macular degeneration (AMD) is characterized by molecular mechanisms responsible for the initiation of choroidal neovascularization (CNV). Inflammatory processes are associated with upregulation of the canonical WNT/beta-catenin pathway in exudative AMD. We focus this review on the link between WNT/beta-catenin pathway activation and neovascular progression in exudative AMD through activation of aerobic glycolysis for production of angiogenic factors. Increased WNT/beta-catenin pathway involves hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). WNT/beta-catenin pathway stimulates PI3K/Akt pathway and then HIF-1alpha which activates glycolytic enzymes: glucose transporter (Glut), pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDH-A), and monocarboxylate lactate transporter (MCT-1). This phenomenon is called aerobic glycolysis or the Warburg effect. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. Cytosolic pyruvate is converted into lactate through the action of LDH-A. In exudative AMD, high level of cytosolic lactate is correlated with increase of VEGF expression, the angiogenic factor of CNV. Photoreceptors in retina cells can metabolize glucose through aerobic glycolysis to protect them against oxidative damage, as cancer cells do.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 11 Boulevard Marie et Pierre Curie, Poitiers, France.
| | | | - Rémy Guillevin
- DACTIM, Laboratoire de Mathématiques et Applications, Université de Poitiers et CHU de Poitiers, UMR CNRS 7348, SP2MI Futuroscope, Chasseneuil-du-Poitou, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications (LMA), UMR CNRS 7348, Université de Poitiers, 11 Boulevard Marie et Pierre Curie, Poitiers, France
- CHU Amiens Picardie, Université Picardie Jules Verne (UPJV), Amiens, France
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Jiang B. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment. Genes Dis 2017; 4:25-27. [PMID: 30258905 PMCID: PMC6136593 DOI: 10.1016/j.gendis.2017.02.003] [Citation(s) in RCA: 154] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 02/04/2017] [Indexed: 12/18/2022] Open
Abstract
Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.
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Affiliation(s)
- Bo Jiang
- Department of Oncology, Avis General Hospital, Beijing, China
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Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression. Oncotarget 2016; 6:37281-99. [PMID: 26484566 PMCID: PMC4741930 DOI: 10.18632/oncotarget.6134] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/23/2015] [Indexed: 12/20/2022] Open
Abstract
Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma.
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Cui W, Lv W, Qu Y, Ma R, Wang YW, Xu YJ, Wu D, Chen X. Discovery of 2-((3-cyanopyridin-2-yl)thio)acetamides as human lactate dehydrogenase A inhibitors to reduce the growth of MG-63 osteosarcoma cells: Virtual screening and biological validation. Bioorg Med Chem Lett 2016; 26:3984-7. [PMID: 27406795 DOI: 10.1016/j.bmcl.2016.06.083] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 06/26/2016] [Accepted: 06/29/2016] [Indexed: 02/01/2023]
Abstract
Lactate dehydrogenase A (LDHA) has emerged as an attractive target in the oncology field. In this paper, we present the identification of 2-((3-cyanopyridin-2-yl)thio)acetamide-containing compounds as LDHA inhibitors. The in vitro enzymatic assay suggested that inhibitor 9 had good inhibitory potency against LDHA with IC50 value as 1.24μM. Cytotoxicity assay showed that inhibitor 9 strongly inhibited the proliferation of cancer cell MG-63 (EC50=0.98μM). These findings indicated that inhibitor 9 could be employed as a lead for developing more potent LDHA inhibitor with anti-proliferative potency.
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Affiliation(s)
- Wei Cui
- Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China
| | - Wei Lv
- Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China
| | - Ying Qu
- Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China
| | - Rui Ma
- Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China
| | - Yi-Wei Wang
- Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China
| | - Yong-Jun Xu
- Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Di Wu
- Department of Orthopedics, Traditional Chinese Medicine Hospital of Harbin, Harbin 150000, Heilongjiang Province, China
| | - Xuanhuang Chen
- Department of Orthopedics, Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China.
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Li J, Wu MF, Lu HW, Chen Q, Lin ZQ, Wang LJ. Pretreatment serum lactate dehydrogenase is an independent prognostic factor for patients receiving neoadjuvant chemotherapy for locally advanced cervical cancer. Cancer Med 2016; 5:1863-72. [PMID: 27350066 PMCID: PMC4971915 DOI: 10.1002/cam4.779] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 03/31/2016] [Accepted: 04/29/2016] [Indexed: 11/15/2022] Open
Abstract
For locally advanced cervical cancer (LACC), hypoxia is a characteristic property. This study aimed to investigate whether baseline lactic dehydrogenase (LDH) level, which is a marker of hypoxia, had clinical value in determining neoadjuvant chemotherapy (NACT) response and prognosis for LACC patients. The study cohort included 418 patients with a median follow‐up of 37.5 months. Cox proportional hazards models were used to assess the prognostic value of baseline LDH levels. Multivariate logistic regression analysis was performed to identify independent predictors of complete response after NACT. Backward stepwise selection with the Akaike information criterion was used to identify factors that could be entered into the multivariate regression model. Compared with patients with LDH levels <252.0 μ/L, patients with LDH levels ≥252.0 μ/L were more likely to have an elevated level of squamous cell carcinoma antigen, lymphatic vascular space involvement, lymph node metastasis, and positive parametrium and achieved lower complete remission rates. Baseline LDH levels ≥252.0 μ/L was an independent prognosticator for recurrence‐free survival (adjusted hazard ratio [HR], 3.56; 95% confidence interval [CI] 2.22–5.69; P < 0.0001) and cancer‐specific survival (adjusted HR, 3.08; 95% CI, 1.89–5.01; P < 0.0001). The predictive value of baseline LDH value remained significant in the subgroup analysis. LDH level ≥252.0 μ/L was identified as an independent predictor of complete remission after NACT (adjusted odds ratio [OR], 0.29; 95% CI, 0.15–0.58; P < 0.0001). Baseline LDH ≥252.0 μ/L is an independent prognostic predictor for patients receiving neoadjuvant chemotherapy for LACC. It helps distinguish patients with different prognosis and select patients who are more likely to benefit from NACT.
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Affiliation(s)
- Jing Li
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.,Team-Based Learning Group of Clinical Study, Sun Yat-Sen University, Guangzhou, 510000, China
| | - Miao-Fang Wu
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Huai-Wu Lu
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qing Chen
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Zhong-Qiu Lin
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Li-Juan Wang
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
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Sun Y, Tao C, Yu F, Yang W, Shan Y, Yu Z, Shi H, Zhou M, Zhang Q, Wu H. Discovery of a novel human lactate dehydrogenase A (LDHA) inhibitor as an anti-proliferation agent against MIA PaCa-2 pancreatic cancer cells. RSC Adv 2016. [DOI: 10.1039/c5ra27736a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A potent LDHA inhibitor with anti-proliferation activity against MIA PaCa-2 cancer cells was first time reported.
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Affiliation(s)
- Yunpeng Sun
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Chonglin Tao
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Fuxiang Yu
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Wenjun Yang
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Yunfeng Shan
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Hongqi Shi
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Mengtao Zhou
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery
- The First Affiliated Hospital of Wenzhou Medical University
- China
| | - Huanhuan Wu
- Department of Infectious Disease
- The First Affiliated Hospital of Wenzhou Medical University
- China
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Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor. Brain Pathol 2015; 26:3-17. [PMID: 26269128 PMCID: PMC8029296 DOI: 10.1111/bpa.12299] [Citation(s) in RCA: 387] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 08/05/2015] [Indexed: 12/14/2022] Open
Abstract
There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non‐neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.
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Affiliation(s)
- Cara J Valvona
- Cellular & Molecular Neuro-oncology Research Group, University of Portsmouth, School of Pharmacy & Biomedical Sciences, Portsmouth, UK
| | - Helen L Fillmore
- Cellular & Molecular Neuro-oncology Research Group, University of Portsmouth, School of Pharmacy & Biomedical Sciences, Portsmouth, UK
| | - Peter B Nunn
- Cellular & Molecular Neuro-oncology Research Group, University of Portsmouth, School of Pharmacy & Biomedical Sciences, Portsmouth, UK
| | - Geoffrey J Pilkington
- Cellular & Molecular Neuro-oncology Research Group, University of Portsmouth, School of Pharmacy & Biomedical Sciences, Portsmouth, UK
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50
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Han J, Zhang L, Guo H, Wysham WZ, Roque DR, Willson AK, Sheng X, Zhou C, Bae-Jump VL. Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling. Gynecol Oncol 2015; 138:668-75. [PMID: 26135947 DOI: 10.1016/j.ygyno.2015.06.036] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 06/23/2015] [Accepted: 06/24/2015] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer. METHODS ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated. RESULTS Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways. CONCLUSIONS Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.
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Affiliation(s)
- Jianjun Han
- Department of Surgical Oncology, Shandong Cancer Hospital and Institute, Jinan, China; Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Lu Zhang
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, China; Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Hui Guo
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, China; Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Weiya Z Wysham
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dario R Roque
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Adam K Willson
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiugui Sheng
- Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Chunxiao Zhou
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Victoria L Bae-Jump
- Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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