Metabolic State of Brain Cancer Stem Cells Significantly Different Than the Cancer Cells They Create8 U2 O; j/ o# H! S) r
/ b4 {9 z( L7 m+ M) B4 j GScienceDaily (Sep. 6, 2011) — The metabolic state of glioma stem cells, which give rise to deadly glioblastomas, is significantly different from that of the brain cancer cells to which they give birth, a factor which helps those stem cells avoid treatment and cause recurrence later. ! w$ ~8 N* s$ K / R+ `: g. l9 A7 [ " |! A1 b+ s/ Z) Y# g; L2 rResearchers with the UCLA Department of Radiation Oncology at UCLA's Jonsson Comprehensive Cancer Center also found for the first time that these glioma stem cells can change their metabolic state at will, from glycolysis, which uses glucose, to oxidative phosphorylation, which uses oxygen. * [. N. K2 c# R9 C) \2 q6 B. O5 ~2 T" ~: u7 Y- z
The glioma stem cells' ability to change their metabolic state at will also allow these stem cells that seed new cancer growth to evade treatment and remain alive, said Dr. Frank Pajonk, an associate professor of radiation oncology and senior author of the study. 5 R/ ~% w: ^5 X( {2 c' n, n, q" B( V% e# e0 n
"We found these cancer stem cells are substantially different in their metabolic states than the differentiated cancer cells they create, and since they act differently, they can't be killed in the same way," Pajonk said. "And as yet, we don't have anything to target these glioma stem cells specifically."! Y- D. V6 M0 n4 z z( C+ L/ A
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The study is published this week in the early online edition of the journal Proceedings of the National Academy of Sciences.0 ?0 d' Y! E) C5 j: A8 |% Y
2 N. r: K! @; M+ gCancer cells take up large amounts of glucose, which fuels their grow and spread and allows them to be differentiated from normal cells under Positron Emission Tomography (PET) scanning, which captures metabolic activity. Pajonk and his team found that the glioma stem cells took up much less glucose, which makes them difficult to detect with PET.0 S$ o7 [5 V, w" e" w4 E; m; s) N; H
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Targeting cancer metabolic pathways as a treatment has gained new interest in recent years. However, these cancer stem cells that take up less glucose could evade those treatments by utilizing glucose more efficiently through oxidative phosphorylation, which would not be targeted by such drugs., n6 d: i' G, [9 f, k
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"If glioma stem cells are indeed important for tumor control, knowledge of the metabolic state of glioma stem cells is needed," the study states.0 u$ m" i1 z {! T- \7 O3 J6 m
" Y6 a; j' c$ n: ^Using a unique imaging system Pajonk and his team developed for glioma stem cells that relies on low enzymatic activity of the proteasome in cancer stem cells, they were able to assess them for metabolic function, including oxygen consumption rates, glucose uptake and other markers. They also found that the glioma stem cells were resistant to radiation, another roadblock to targeting these cells with conventional treatments. / b' J. f, a6 K) N3 j* ~9 R( k & D$ d% Q1 P" ~: c. i5 [9 HPajonk and his team concluded that glioma stem cells rely mainly on oxidative phosphorylation for energy. But they found if the stem cells were challenged, they could switch on additional metabolic pathways.7 V4 h+ j6 G3 H2 j4 S; G- c
! ]- i( d4 P) [! {) PThe study also shows for the first time that low expression of proteasome sub-units, an indicator of large numbers of glioma stem cells in the tumor, predicts unfavorable treatment outcomes for those patients. + f. P% E* S$ F# t! c/ K9 O , {8 e9 H) D/ f4 b. g7 O! }6 \. ^"What I think is really exciting is we have here for the first time a novel cancer stem cell marker in glioma, which gives us an additional tool to look for these cells and come up with therapies that target them," said Pajonk, who also is a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.& M( ]: \- U' L3 A% s1 i
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This study was funded by the National Cancer Institute. & \4 a- f' K, u' |( o+ z, G8 D. n4 p" g( }" i7 ~9 H) g http://www.sciencedaily.com/releases/2011/09/110906164309.htm作者: naturalkillerce 时间: 2011-9-20 17:18
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3 G9 e4 K/ ~# w. P9 u+ D研究揭示糖代谢p53调控机理 & c# x( e1 \! i" K. ? v! q0 b$ \* w
2月20日,国际著名学术期刊《自然—细胞生物学》(Nature Cell Biology)在线发表了中国科学技术大学生命科学学院吴缅教授和美国宾夕法尼亚大学医学院杨小鲁教授的合作研究结果:p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase。该杂志同期以News and Views的形式发表了题为p53 guards the metabolic pathway less travelled的长篇评论。0 o' \, B# a/ d" k: z6 A/ u J
1 ]# T8 m- Z# x( {6 r肿瘤抑制因子p53在调控磷酸戊糖途径(pentose phosphate pathway, PPP)中发挥了重要的作用。p53是迄今为止细胞中最为重要的肿瘤抑制因子之一,它在细胞生长发育中的周期调控、DNA修复以及细胞凋亡等重要细胞过程中发挥着关键作用。近年来,科学家发现p53在细胞代谢,尤其在糖代谢中也起着重要作用。 $ i' W- y2 v4 \+ t; v % J1 n: z |/ ~! X) }- J吴缅研究组和杨小鲁实验室的最新工作证明,p53可以与磷酸戊糖途径上的第一步反应的关键酶——葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase,G6PD)相结合,并且抑制它的活性。在正常情况下,p53参与阻止这一途径的进行,细胞中的葡萄糖因此被主要用于进行酵解和三羧酸循环;在p53发生突变或缺失的肿瘤细胞中,由于p53的突变使它失去与G6PD结合的能力和对G6PD的抑制,细胞中利用葡萄糖的另一代谢途径即磷酸戊糖途径因此加速进行,大量消耗葡萄糖,这就部分解释了自19世纪20年代末科学家所提出的Warburg现象。另外,由于PPP的加速,产生大量NAPDH及戊糖(DNA的组份原料),可以满足肿瘤细胞快速生长所需要的大量的DNA复制。此外,该研究还第一次提出:p53除了具有转录活性外,还具有催化功能,它通过与底物瞬时结合,以“hit-and-run”的模式使G6PD酶的活性降低。' P8 E1 F0 H5 Y |8 J, `
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论文的第一作者是吴缅教授课题组的博士生江鹏和杜文静,目前,他们在美国宾夕法尼亚大学医学院从事博士后研究。该研究得到国家自然科学基金委、中科院以及科技部的资助。(来源:中国科技大学) - r: @- w$ P( u( b
2 @6 Q9 e8 B- n; ]0 o8 p新的见解:p53蛋白控制葡萄糖的代谢途径中的分子十字路口 ' m4 M a* h2 R( U v; l% cPublished on March 3, 2011 ' b# S @$ p+ T; i( x' L) vhttp://www.news-medical.net/news ... lified-Chinese.aspx ) ] \* G1 T/ X. r! ]蛋白p53基因是最常见的突变在人类癌症。它编码一种肿瘤抑制基因,和传统的研究人员假设,这主要是由于成蛋白质的基因是如何调节的行为。现在,研究人员在宾夕法尼亚州大学医学表明,该蛋白具有至少一个其他生化活性的学校:控制糖葡萄糖的新陈代谢,身体的主要燃料来源之一。这些新的见解上研究蛋白质可能被用来开发新的癌症疗法。 4 f( i8 L0 h, W: f( \9 d4 d8 A- f1 n: q) Q0 t
艾布拉姆森家庭癌症研究所癌症生物学副教授,在中国和南京理工大学,在自然本期报告的科学和技术大学与吴勉,博士,细胞生物学博士,鲁阳,p53基因控制分子在细胞的葡萄糖代谢途径中的一个十字路口。 - p) L+ C9 m7 R7 k9 r
- H2 v `; @3 F0 H3 g他们发现,p53基因物理结合,并抑制一种酶 - 葡萄糖-6 - 磷酸脱氢酶(G6PD),催化通路的第一步。如果P53不能尽其意的工作,细胞生长失控。 ^+ u5 T/ m9 p9 N & l! o8 v' i( @$ ]+ P; t阻断这一途径分流葡萄糖远离能源储存和对遗传大厦和血脂,促进细胞增殖。 p53的正常供应,以打击迫使细胞占用较少的葡萄糖分子和细胞繁殖的合成。 9 R, ?8 W$ B8 e T3 K; F6 T" a% X6 j; ^: F3 K8 c4 z% E+ S& a
在肿瘤,其中超过一半携带p53基因的突变,该路由功能被取消,使细胞构建与放弃的生物量和鸿沟。 0 R. u9 F. `4 _$ F" C1 s$ ?/ C& ~* A
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这一发现提供了一个生化解释在华的影响,这解释癌细胞如何,无论哪种类型,似乎不可避免地提高他们的葡萄糖消耗,但在能源效率的方式不。 7 M, ~( q {% A/ Q5 O8 V/ B7 q9 } ( K6 |$ [9 X, C+ Y. d2 p V“我们发现,癌细胞中最常见的基因突变之间的连接以及如何突变有助于肿瘤的生长,”杨说。 ' ?' u; `/ U+ u* R: S