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      • Record: found
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      Expression of glutamine metabolism-related proteins in thyroid cancer

      research-article
      Author(s): 1 , 1 , 1
      Publication date (Electronic):
      Journal: Oncotarget
      Publisher: Impact Journals LLC
      Keywords: thyroid cancer, glutamine, metabolism, stroma, pathology

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          Abstract

          Purpose

          This study aimed to investigate the expression of glutamine metabolism-related protein in tumor and stromal compartments among the histologic subtypes of thyroid cancer.

          Results

          GLS1 and GDH expression in tumor and stromal compartments were the highest in AC than in other subtypes. Tumoral ASCT2 expression was higher in MC but lower in FC (p < 0.001). In PTC, tumoral GLS1 and tumoral GDH expression was higher in the conventional type than in the follicular variant (p = 0.043 and 0.001, respectively), and in PTC with BRAF V600E mutation than in PTC without BRAF V600E mutation (p<0.001). Stromal GDH positivity was the independent factor associated with short overall survival (hazard ratio: 21.48, 95% confidence interval: 2.178-211.8, p = 0.009).

          Methods

          We performed tissue microarrays with 557 thyroid cancer cases (papillary thyroid carcinoma [PTC]: 344, follicular carcinoma [FC]: 112, medullary carcinoma [MC]: 70, poorly differentiated carcinoma [PDC]: 23, and anaplastic carcinoma [AC]: 8) and 152 follicular adenoma (FA) cases. We performed immunohistochemical staining of glutaminolysis-related proteins (glutaminase 1 [GLS1], glutamate dehydrogenase [GDH], and amino acid transporter-2 [ASCT-2]).

          Conclusion

          Glutamine metabolism-related protein expression differed among the histologic subtypes of thyroid cancer.

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          Most cited references56

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          On the origin of cancer cells.

          O WARBURG (1956)
          Article 0 comments Cited 2462 times – based on 0 reviews     Review now
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            Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.

            Matt I Gross, Susan D Demo, Jennifer B. Dennison … (2014)
            Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.
            Article 0 comments Cited 393 times – based on 0 reviews     Review now
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              The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.

              Fabiana Schwartzenberg-Bar-Yoseph, Michal Armoni, Eddy Karnieli (2004)
              Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.
              Article 0 comments Cited 210 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 16 August 2016
                Publication date (Electronic): 18 July 2016
                Volume: 7
                Issue: 33
                Pages: 53628-53641
                Affiliations
                1 Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
                Author notes
                Correspondence to: Ja Seung Koo, kjs1976@ 123456yuhs.ac
                Article
                Publisher ID: 10682
                DOI: 10.18632/oncotarget.10682
                PMC ID: 5288210
                PubMed ID: 27447554
                SO-VID: 2505354e-2d59-46a5-8229-7f9067005af6
                Copyright © Copyright: © 2016 Kim et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 1 February 2016
                Date accepted : 9 July 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: thyroid cancer,glutamine,metabolism,stroma,pathology
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: thyroid cancer, glutamine, metabolism, stroma, pathology

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