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CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4

Cancer cells rely on glycolysis to maintain high levels of anabolism. However, the metabolism of glucose via glycolysis in cancer cells is frequently incomplete and results in the accumulation of acidic metabolites such as pyruvate and lactate. Thus, the cells have to develop strategies to alleviate...

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Autores principales: Wang, L, Zhou, H, Wang, Y, Cui, G, Di, L-j
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669780/
https://www.ncbi.nlm.nih.gov/pubmed/25633289
http://dx.doi.org/10.1038/cddis.2014.587
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author Wang, L
Zhou, H
Wang, Y
Cui, G
Di, L-j
author_facet Wang, L
Zhou, H
Wang, Y
Cui, G
Di, L-j
author_sort Wang, L
collection PubMed
description Cancer cells rely on glycolysis to maintain high levels of anabolism. However, the metabolism of glucose via glycolysis in cancer cells is frequently incomplete and results in the accumulation of acidic metabolites such as pyruvate and lactate. Thus, the cells have to develop strategies to alleviate the intracellular acidification and maintain the pH stability. We report here that glutamine consumption by cancer cells has an important role in releasing the acidification pressure associated with cancer cell growth. We found that the ammonia produced during glutaminolysis, a dominant glutamine metabolism pathway, is critical to resist the cytoplasmic acidification brought by the incomplete glycolysis. In addition, C-terminal-binding protein (CtBP) was found to have an essential role in promoting glutaminolysis by directly repressing the expression of SIRT4, a repressor of glutaminolysis by enzymatically modifying glutamate dehydrogenase in mitochondria, in cancer cells. The loss of CtBP in cancer cells resulted in the increased apoptosis due to intracellular acidification and the ablation of cancer cell metabolic homeostasis represented by decreased glutamine consumption, oxidative phosphorylation and ATP synthesis. Importantly, the immunohistochemistry staining showed that there was excessive expression of CtBP in tumor samples from breast cancer patients compared with surrounding non-tumor tissues, whereas SIRT4 expression in tumor tissues was abolished compared with the non-tumor tissues, suggesting CtBP-repressed SIRT4 expression contributes to the tumor growth. Therefore, our data suggest that the synergistically metabolism of glucose and glutamine in cancer cells contributes to both pH homeostasis and cell growth. At last, application of CtBP inhibitor induced the acidification and apoptosis of breast cancer cells and inhibited glutaminolysis in engrafted tumors, suggesting that CtBP can be potential therapeutic target of cancer treatment.
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spelling pubmed-46697802015-12-08 CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4 Wang, L Zhou, H Wang, Y Cui, G Di, L-j Cell Death Dis Original Article Cancer cells rely on glycolysis to maintain high levels of anabolism. However, the metabolism of glucose via glycolysis in cancer cells is frequently incomplete and results in the accumulation of acidic metabolites such as pyruvate and lactate. Thus, the cells have to develop strategies to alleviate the intracellular acidification and maintain the pH stability. We report here that glutamine consumption by cancer cells has an important role in releasing the acidification pressure associated with cancer cell growth. We found that the ammonia produced during glutaminolysis, a dominant glutamine metabolism pathway, is critical to resist the cytoplasmic acidification brought by the incomplete glycolysis. In addition, C-terminal-binding protein (CtBP) was found to have an essential role in promoting glutaminolysis by directly repressing the expression of SIRT4, a repressor of glutaminolysis by enzymatically modifying glutamate dehydrogenase in mitochondria, in cancer cells. The loss of CtBP in cancer cells resulted in the increased apoptosis due to intracellular acidification and the ablation of cancer cell metabolic homeostasis represented by decreased glutamine consumption, oxidative phosphorylation and ATP synthesis. Importantly, the immunohistochemistry staining showed that there was excessive expression of CtBP in tumor samples from breast cancer patients compared with surrounding non-tumor tissues, whereas SIRT4 expression in tumor tissues was abolished compared with the non-tumor tissues, suggesting CtBP-repressed SIRT4 expression contributes to the tumor growth. Therefore, our data suggest that the synergistically metabolism of glucose and glutamine in cancer cells contributes to both pH homeostasis and cell growth. At last, application of CtBP inhibitor induced the acidification and apoptosis of breast cancer cells and inhibited glutaminolysis in engrafted tumors, suggesting that CtBP can be potential therapeutic target of cancer treatment. Nature Publishing Group 2015-01 2015-01-29 /pmc/articles/PMC4669780/ /pubmed/25633289 http://dx.doi.org/10.1038/cddis.2014.587 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Wang, L
Zhou, H
Wang, Y
Cui, G
Di, L-j
CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title_full CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title_fullStr CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title_full_unstemmed CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title_short CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4
title_sort ctbp maintains cancer cell growth and metabolic homeostasis via regulating sirt4
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669780/
https://www.ncbi.nlm.nih.gov/pubmed/25633289
http://dx.doi.org/10.1038/cddis.2014.587
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