title: SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2.
abstract: Lung cancer is the leading cause of death worldwide and associated with dismal prognoses. As a major mitochondrial deacetylase, SIRT3 regulates the activity of enzymes to coordinate global shifts in cellular metabolism and has important implications for tumor growth. Its role as a tumor suppressor or an oncogene in lung cancer is unclear, especially in non-small cell lung carcinoma (NSCLC). To identify the mechanism of SIRT3-interacting proteins, we performed a yeast two-hybrid screen using a human lung cDNA library. One of the positive clones encoded the full-length cDNA of the nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) gene and the interaction between SIRT3 and NMNAT2 was identified. The interaction on growth, proliferation, apoptosis of NSCLC cell lines, and energy metabolism related to SIRT3 were investigated. Screening from the library resulted in NMNAT2 gene. We found that NMNAT2 interacts with SIRT3 both in vitro and in vivo; SIRT3 binds to NMNAT2 deacetylating it. Downregulation of SIRT3 inhibited acetylation of NMNAT2 and NAD+ synthesis activity of the enzyme. Low expression of SIRT3 significantly inhibited mitotic entry, growth and proliferation of NSCLC cell lines and promoted apoptosis, which was related to energy metabolism involving in the interaction between SIRT3 and NMNAT2. Taken together, our results strongly suggest that the binding of SIRT3 with NMNAT2 is a novel regulator of cell proliferation and apoptosis in NSCLC cell lines, implicating the interaction between SIRT3 and NMNAT2, energy metabolism associated with SIRT3.
authors.affiliation: Department of Radiation Oncology, Air Force General Hospital, Beijing 100142, P.R. China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Li
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Feng
authors.forename: Weizhang
authors.initials: W
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Jinqian
authors.initials: J
authors.lastname: Zhang
authors.forename: Tingyi
authors.initials: T
authors.lastname: Xia
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D004734:Energy Metabolism; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*; D010101:Oxygen Consumption; D011499:Protein Processing, Post-Translational; D056566:Sirtuin 3 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
chemical_list: C484008:NMNAT2 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C466093:SIRT3 protein, human; D056566:Sirtuin 3
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10230-10235
references.pmid: 16790548
references.citation: J Biol Chem. 2010 Dec 17;285(51):40387-96
references.pmid: 20943658
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: J Biol Chem. 1997 Aug 22;272(34):21010-7
references.pmid: 9261102
references.citation: N Engl J Med. 2002 Jan 10;346(2):92-8
references.pmid: 11784875
references.citation: Methods Enzymol. 2001;331:281-92
references.pmid: 11265470
references.citation: Exp Gerontol. 2003 Oct;38(10):1065-70
references.pmid: 14580859
references.citation: Trends Mol Med. 2012 Sep;18(9):516-23
references.pmid: 22749020
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
references.pmid: 18794531
references.citation: J Cereb Blood Flow Metab. 2007 Feb;27(2):304-15
references.pmid: 16736046
references.citation: Front Biosci. 2007 Jan 01;12:2728-34
references.pmid: 17127275
references.citation: J Clin Oncol. 2001 Jul 1;19(13):3210-8
references.pmid: 11432888
references.citation: Fed Proc. 1981 Jun;40(8):2311-6
references.pmid: 7238911
references.citation: J Biol Chem. 2003 May 16;278(20):18426-33
references.pmid: 12626504
references.citation: Cancer Cell. 2011 Mar 8;19(3):416-28
references.pmid: 21397863
references.citation: Nat Cell Biol. 2004 Aug;6(8):731-40
references.pmid: 15235609
references.citation: J Cell Biol. 2005 Aug 1;170(3):349-55
references.pmid: 16043516
references.citation: Cancer Gene Ther. 2013 Jul;20(7):403-12
references.pmid: 23764899
references.citation: J Biol Chem. 2010 Jan 29;285(5):3133-44
references.pmid: 19940131
references.citation: Cell. 2003 Sep 5;114(5):585-98
references.pmid: 13678582
references.citation: Mol Cell Biol. 2008 Oct;28(20):6384-401
references.pmid: 18710944
references.citation: Genomics. 2001 Apr 15;73(2):211-22
references.pmid: 11318611
references.citation: Neurochem Int. 2010 Jan;56(1):101-6
references.pmid: 19778564
references.citation: Biochem Biophys Res Commun. 2002 Oct 4;297(4):835-40
references.pmid: 12359228
references.citation: J Biol Chem. 2005 Apr 8;280(14):13560-7
references.pmid: 15653680
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:275-82
references.pmid: 19076449
references.citation: Science. 2004 Aug 13;305(5686):1010-3
references.pmid: 15310905
references.citation: J Clin Oncol. 2003 Aug 15;21(16):3016-24
references.pmid: 12837811
references.citation: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references.pmid: 15761078
references.citation: J Biol Chem. 2010 Jun 11;285(24):18868-76
references.pmid: 20388704
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Cancer Res. 2005 Nov 15;65(22):10457-63
references.pmid: 16288037
references.citation: J Biol Chem. 2005 Oct 28;280(43):36334-41
references.pmid: 16118205
references.citation: J Clin Oncol. 2002 Nov 1;20(21):4285-91
references.pmid: 12409326
references.citation: PLoS Biol. 2010 Jan 26;8(1):e1000300
references.pmid: 20126265
references.citation: J Clin Invest. 2009 Sep;119(9):2758-71
references.pmid: 19652361
references.citation: Life Sci. 2006 Nov 10;79(24):2293-302
references.pmid: 16935310
references.citation: Clin Lung Cancer. 2012 Jul;13(4):252-66
references.pmid: 22154278
references.citation: Neuromolecular Med. 2002;2(2):215-31
references.pmid: 12428812