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1、代謝組學(xué)在腫瘤研究中的應(yīng)用二代謝組學(xué)概況代謝與腫瘤的關(guān)系代謝組學(xué)在腫瘤研究中的應(yīng)用1. 代謝組學(xué)1-1 代謝組學(xué)的定義代謝組學(xué) (metabonomics): 某一生物或細(xì)胞所有低分子質(zhì)量代謝產(chǎn)物進(jìn)行定性和定量檢測, 分析活細(xì)胞中代謝物譜變化的研究領(lǐng)域生物標(biāo)本: 血液、尿液等體液, 組織、細(xì)胞提取物、細(xì)胞培養(yǎng)液1-2 代謝組學(xué)分析技術(shù)-NMRNMR光譜: NMR技術(shù)是最早被用于代謝組學(xué)研究的技術(shù)之一其利用原子核在磁場中的能量變化來獲得相關(guān)信息。目前常用的有 1H-NMR、 13C-NMR和31P-NMR1-2 代謝組學(xué)分析技術(shù)-NMR1-2 代謝組學(xué)分析技術(shù)-NMR1-2 代謝組學(xué)分析技術(shù)-N
2、MRWarburg, O. On the origin of cancer cells. Science 123, 309314 (1956)The Warburg Effect1-2 代謝組學(xué)分析技術(shù)-MSMS: Mass Spectrometry, 質(zhì)譜 基本原理是: 將樣品中各組分電離成離子束, 進(jìn)入質(zhì)量分析器聚集而得到MS圖譜,以確定其質(zhì)量。 1-2 代謝組學(xué)分析技術(shù)-MS1-2 代謝組學(xué)分析技術(shù)-MSMS: Mass Spectrometry, 質(zhì)譜需聯(lián)合色譜技術(shù)對樣品進(jìn)行前期分離( 1 ) GC MS聯(lián)用 : GC技術(shù)是以氣體作為流動相的色 譜法常用于分離揮發(fā)性化合物。( 2 )
3、LC MS聯(lián)用 : LC技 術(shù)是 以液 體作 為流 動相 的色 譜 法適用于分離低 揮發(fā)性或非揮發(fā)性、熱穩(wěn)定性 差的物質(zhì)。2. 代謝與腫瘤的關(guān)系 2-1 Tumor glucose metabolic phenotypes: Glucose glycolysis and oxidative phosphorylationWarburg, O. On the origin of cancer cells. Science 123, 309314 (1956)The Warburg Effect 2-2 Tumor glucose metabolic phenotypes: The pentose
4、 phosphate pathway 2-3 Tumor lipid metabolic phenotypes: Simplified overview of tumor lipid metabolismJournal of Nuclear Medicine 2008, Vol. 49 No. Suppl_2 43S-63S 2-4 Tumor amino acid metabolic phenotypes: Regulation of glycolysis, glutaminolysis and de novo nucleotide biosynthesis in tumor cells.
5、Current Opinion in Genetics & Development Volume 19, Issue 1, February 2009Cell September 5, 2008, 134,703-707Cancer Cell June 2008,13,472-4822. 1 P53 與腫瘤代謝 2-1. p53 in tumor cell metabolism: glycolysisFigure 1 The three metabolic fates of glucose in cells and the role for p53 in glucose metabolismn
6、ature cell biology VOLUME 13 | NUMBER 3 | MARCH 2011 Bensaad, K. et al. Cell 126, 107120 (2006). 2-1 p53 in tumor cell metabolism: glycolysisOne target of p53 known to affect glucose glycolysis is TIGAR 2-1 p53 in tumor cell metabolism: glycolysisOne target of p53 known to affect glucose glycolysis
7、is TIGAR 2-1 p53 in tumor cell metabolism: glycolysisOne target of p53 known to affect glucose glycolysis is TIGARBensaad, K. et al. Cell 126, 107120 (2006)the four genes (pfkfb14) encoding the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) 2-1 p53 in tumor cell metabol
8、ism: oxidative phosphorylationp53Cell 126, July 14, 2006One target of p53 known to affect glucose oxidative phosphorylation is SCO2 2-1 p53 in tumor cell metabolism: oxidative phosphorylationOne target of p53 known to affect glucose oxidative phosphorylation is SCO2 2-1 p53 in tumor cell metabolism:
9、 pentose phosphate pathwayFigure 1 The three metabolic fates of glucose in cells and the role for p53 in glucose metabolismnature cell biology VOLUME 13 | NUMBER 3 | MARCH 2011 2-1 p53 in tumor cell metabolism: pentose phosphate pathway 2-1 p53 in tumor cell metabolism: pentose phosphate pathwayFigu
10、re 1 . p53 deciency correlates with increases in PPP flux, glucose consumption and lactate production 2-1 p53 in tumor cell metabolism: pentose phosphate pathwayFigure 2. p53 regulates NADPH levels, lipid accumulation and G6PD activity 2-1 p53 in tumor cell metabolism: pentose phosphate pathwayFigur
11、e 3 p53 interacts with G6PD and inhibits its activity independently of transcription. 2-1 p53 in tumor cell metabolism: pentose phosphate pathwayFigure 4 p53 inhibits the formation of dimeric G6PD holoenzyme.p53 regulation of energy metabolism 2-1 p53 in tumor cell metabolism 2-1 p53 in tumor cell m
12、etabolism: glutamine metabolismBiochemistry of glutamine metabolism (main pathways): glutaminase 2-1 p53 in tumor cell metabolism: glutamine metabolism 2-1 p53 in tumor cell metabolism: glutamine metabolismModel for regulation of intracellular ROS levels by GLS2.2. 2 HIF-1 與腫瘤代謝 2-2 HIF-1 in tumor c
13、ell metabolismHIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010 Feb;20(1):51-6. 2-2 HIF-1 in tumor cell metabolism HIF-1: activating transcription of genes encoding glucose transporters and glycolytic enzymeExpression of genes encoding glucose transporters and glycolytic
14、 enzymes. The glycolytic pathway is shown at left. Symbols for genes encoding the respective enzymes are coded by font according to the mRNA expression pattern (normalized to 18S rRNA) in ES cells cultured under nonhypoxic (N) or hypoxic (H) conditions for 16 hr (lanes 16 at right) as follows: (1) (
15、bold) increased expression in hypoxic Hif1a+/+ cells, loss of induction in Hif1a+/ cells, and loss of basal and induced expression in Hif1a/ cells; (2) (bold and italicized) no effect of hypoxia on expression in Hif1a+/+ cells but decreased expression in hypoxic Hif1a+/ and Hif1a/ cells; (3) (italic
16、ized) no effect of hypoxia on expression in Hif1a+/+ cells but decreased expression in hypoxic and nonhypoxic Hif1a/ cells; (4) (plain) no effect of hypoxia or HIF-1 deficiency on expression. mRNA expression in Hep3B cells was also assayed (lanes 7,8). The indicated genes encode the following protei
17、ns: (GLUT1 and GLUT3) glucose transporter 1 and 3; (HK1 and HK2) hexokinase 1 and 2; (GPI) glucosephosphate isomerase; (PFKL) phosphofructokinase L; (ALDA and ALDC) aldolase A and C; (TPI) triosephosphate isomerase; (GAPDH) glyceraldehyde-3-phosphate dehydrogenase; (PGK1) phosphoglycerate kinase 1;
18、(PGM) phosphoglucomutase; (ENO1) enolase 1; (PKM) pyruvate kinase M; (LDHA) lactate dehydrogenase A. GLUCOSE (EXT) and GLUCOSE (INT) refer to extracellular and intracellular glucose, respectively,Genes Dev. 1998 Jan 15;12(2):149-62. 2-2 HIF-1 in tumor cell metabolism HIF-1: up-regulated the plasma m
19、embrane lactate transporter MCT4The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1a-dependent mechanism. J Biol Chem 2006, 281:9030-9037. 2-2 HIF-1 in tumor cell metabolismPDKPDHHIF-1-mediated expression of pyruvate dehydrogenase kinase: A metaboli
20、c switch required for cellular adaptation to hypoxia CELL METABOLISM 3, 177185, MARCH 2006HIF-1mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumptionCELL METABOLISM 3, 187197, MARCH 2006 2-2 HIF-1 in tumor cell metabolismFigure 1. HIF-1-dependent induction of PDK1
21、 expression in hypoxic cellsFigure 6. Coordinate regulation of hypoxia-induced metabolic switches by HIF-1 2-2 HIF-1 in tumor cell metabolism2. 3 mTOR 與腫瘤代謝 2-3 mTOR in tumor cell metabolism Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glyc
22、olysis and tumor growth 2-3 mTOR in tumor cell metabolism: PPP/lipid synthesis Molecular Cell, Volume 39, Issue 2, 171-183, 30 July 2010Highlights: 1. mTORC1 stimulates glucose uptake and glycolysis through HIF1 2. mTORC1 stimulates the pentose phosphate pathway and lipid biosynthesis through SREBP1
23、SREBP: sterol regulatory element-binding protein, SREBPs belong to the basic helix-loop-helixleucine zipper (bHLH-Zip) family of transcription factors 2-3 mTOR in tumor cell metabolism: PPP/lipid synthesis J Clin Invest. 2002;109(9):11251131 2-3 mTOR in tumor cell metabolism: lipid synthesis mTORC1 signaling will contribute to tumor development and progression, the stimulation of ribosome biogenesis leading to an overall increase in protein synthesis is like
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