title: CtBP maintains cancer cell growth and metabolic homeostasis via regulating SIRT4.
abstract: 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.
authors: University of Macau, Macau, SAR of People's Republic of China.
authors: L
authors: L
authors: Wang
authors: School of life Sciences, Anhui Medical University, Hefei, Anhui Province, People's Republic of China.
authors: H
authors: H
authors: Zhou
authors: Institute of Chinese Medical Sciences, University of Macau, Macau, SAR of People's Republic of China.
authors: Y
authors: Y
authors: Wang
authors: 1] Institute of Chinese Medical Sciences, University of Macau, Macau, SAR of People's Republic of China [2] Bioengineering department, Zunyi Medical college, Zhuhai, Guangdong Province, People's Republic of China.
authors: G
authors: G
authors: Cui
authors: University of Macau, Macau, SAR of People's Republic of China.
authors: L-J
authors: LJ
authors: Di
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D037761:Sirtuins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D005973:Glutamine; C014632:2-keto-4-methylthiobutyric acid; D008715:Methionine; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C525357:SIRT4 protein, human; D037761:Sirtuins
references: Nature. 2003 Apr 17;422(6933):735-8
references: 12700765
references: Nat Rev Mol Cell Biol. 2010 Jan;11(1):50-61
references: 19997129
references: FEBS Lett. 2014 May 2;588(9):1743-8
references: 24657618
references: J Cell Biol. 2007 Jul 2;178(1):93-105
references: 17606868
references: Sci Signal. 2010;3(119):ra31
references: 20424262
references: Cancer Res. 2010 Nov 15;70(22):8981-7
references: 21045145
references: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
references: 20421486
references: Cell Metab. 2008 Jan;7(1):11-20
references: 18177721
references: Genes Dev. 2008 May 15;22(10):1397-409
references: 18483224
references: PLoS Genet. 2011 Aug;7(8):e1002229
references: 21852960
references: J Biol Chem. 2010 Oct 15;285(42):32405-14
references: 20705609
references: Cancer Discov. 2012 Oct;2(10):881-98
references: 23009760
references: Cell. 2013 May 9;153(4):840-54
references: 23663782
references: Science. 2010 Dec 3;330(6009):1340-4
references: 21127244
references: Cell Metab. 2012 Jan 4;15(1):110-21
references: 22225880
references: Mol Cell. 2009 Nov 13;36(3):469-76
references: 19917254
references: Cancer Cell. 2010 Sep 14;18(3):207-19
references: 20832749
references: Mol Cell. 2013 Jan 24;49(2):310-21
references: 23201122
references: Biochem Biophys Res Commun. 1992 Jul 31;186(2):782-9
references: 1323291
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Trends Biochem Sci. 2010 Aug;35(8):427-33
references: 20570523
references: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):829-33
references: 17213307
references: Int J Cell Biol. 2013;2013:647975
references: 23762064
references: Cell Res. 2013 May;23(5):635-44
references: 23337585
references: Miner Electrolyte Metab. 1990;16(5):322-30
references: 2283995
references: Biochim Biophys Acta. 2014 Jan;1837(1):51-62
references: 23891695
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9202-7
references: 12872005
references: Cell Cycle. 2010 Sep 15;9(18):3740-50
references: 20930544
references: Nature. 2013 Apr 4;496(7443):101-5
references: 23535601
references: Mol Cell Biol. 2013 Apr;33(7):1368-82
references: 23339872
references: Cell Metab. 2011 Oct 5;14(4):443-51
references: 21982705
references: Mol Cell Biol. 2002 Aug;22(15):5296-307
references: 12101226
references: Cancer Cell. 2012 Mar 20;21(3):297-308
references: 22439925
references: J Gen Physiol. 2012 Jun;139(6):415-23
references: 22641636
references: Cell. 2006 Sep 8;126(5):941-54
references: 16959573
references: Diabetes. 2013 Dec;62(12):4122-31
references: 23990359
references: Am J Pathol. 2013 Apr;182(4):1055-64
references: 23438473
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19345-50
references: 18032601
references: J Mol Med (Berl). 2011 Mar;89(3):229-36
references: 21301794
references: Nat Struct Mol Biol. 2010 Dec;17(12):1406-13
references: 21102443
references: Science. 2009 May 22;324(5930):1029-33
references: 19460998
references: Nat Commun. 2013;4:1449
references: 23385593
references: Annu Rev Cell Dev Biol. 2011;27:441-64
references: 21985671
references: Nat Rev Cancer. 2009 Jun;9(6):400-14
references: 19440234
references: Oncogene. 2007 Nov 29;26(54):7544-51
references: 17546044
references: J Biol Chem. 2014 Feb 14;289(7):4135-44
references: 24368766
references: Int J Biochem Cell Biol. 2011 May;43(5):693-6
references: 21281737
references: Cancer Cell. 2013 Apr 15;23(4):450-63
references: 23562301