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      Suppression of lactate dehydrogenase A compromises tumor progression by downregulation of the Warburg effect in glioblastoma

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          Abstract

          Reprogrammed glucose metabolism is an emerging hallmark of cancer cells, which show a unique metabolic phenotype known as the Warburg effect. Lactate dehydrogenase A (LDHA), a key enzyme in the glycolytic process, executes the final step by conversion of lactate into pyruvate. However, little is known about the roles of LDHA in human glioblastoma (GBM). In this study, we aimed to determine the effects of LDHA and elucidate related underlying mechanisms. Data derived from Oncomine database showed that LDHA is commonly upregulated in GBM tissues in comparison with corresponding normal controls. Silencing of LDHA expression resulted in reduced glycolysis, decreased cell growth, increased cell apoptosis, and attenuated invasive ability. In the presence of 2-deoxyglucose, a glycolysis inhibitor, the oncogenic activities of LDHA were completely blocked. These findings provide evidence of the cellular functions of LDHA in the progression of GBM and suggest that LDHA might act as a potential therapeutic target for GBM treatment.

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          Links between metabolism and cancer.

          Chi Dang (2012)
          Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.
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            Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth.

            H. Liu, D. Yu, YUEMIN DING … (2009)
            ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.
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              A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer.

              Zhenggang Zhu, Jun Zhang, Helena J Du Plessis … (2014)
              Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effect on aerobic glycolysis in pancreatic tumors. Therefore, we investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling in aerobic glycolysis in pancreatic cancer cells. Expression of KLF4 and lactate dehydrogenase A (LDHA) in 70 primary pancreatic tumors and 10 normal pancreatic tissue specimens was measured. Also, the underlying mechanisms of altered KLF4 expression and its impact on aerobic glycolysis in pancreatic cancer cells were investigated. We found a negative correlation between KLF4 and LDHA expression in pancreatic cancer cells and tissues and that their expression was associated with clinicopathologic features of pancreatic cancer. KLF4 underexpression and LDHA overexpression were correlated with disease stage and tumor differentiation. Experimentally, KLF4 overexpression significantly attenuated the aerobic glycolysis in and growth of pancreatic cancer cells both in vitro and in orthotopic mouse models, whereas knockdown of KLF4 expression had the opposite effect. Enforced KLF4 expression decreased LDHA expression, whereas small interfering RNA-mediated knockdown of KLF4 expression had the opposite effect. Mechanistically, KLF4 bound directly to the promoter regions of the LDHA gene and negatively regulated its transcription activity. Dysregulated signaling in this novel KLF4/LDHA pathway significantly impacts aerobic glycolysis in and development and progression of pancreatic cancer. ©2014 American Association for Cancer Research.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Neuroreport
                Journal ID (iso-abbrev): Neuroreport
                Journal ID (publisher-id): WNR
                Title: Neuroreport
                Publisher: Lippincott Williams & Wilkins
                ISSN (Print): 0959-4965
                ISSN (Electronic): 1473-558X
                Publication date (Print): 20 January 2016
                Publication date (Electronic): 06 January 2016
                Volume: 27
                Issue: 2
                Pages: 110-115
                Affiliations
                [a ]The Third Department of Radiotherapy
                [b ]Department of Neurosurgery
                [c ]The Fifth Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang
                [d ]Department of Orthopaedics, Boye County Hospital of Hebei Province, Baoding, China
                Author notes
                Correspondence to Shuchai Zhu, PhD, The Third Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, #12, Jiankang Road, Shijiazhuang 050011, China Tel/fax: +86 0311 86095588; e-mail: sczhu@ 123456heinfo.net
                Article
                DOI: 10.1097/WNR.0000000000000506
                PMC ID: 4712768
                PubMed ID: 26694942
                SO-VID: b4525678-0dde-4f06-bf25-c8e29e3c9934
                Copyright © Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 25 September 2015
                Date accepted : 10 November 2015
                Categories
                Subject: Cellular, Molecular and Developmental Neuroscience
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: apoptosis,growth,invasion,lactate dehydrogenase a,warburg effect
                Data availability:
                Keywords: apoptosis, growth, invasion, lactate dehydrogenase a, warburg effect

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