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ATP Consumption Promotes Cancer Metabolism ATP的消耗促进肿瘤代谢
Cancer cells metabolize glucose by aerobic glycolysis, a phenomenon known as the Warburg
effect. 癌症细胞的代谢是通过糖的有氧酵解来完成的，这个现象称为瓦伯格效应。
Fang et al. (2010) show that the endoplasmic reticulum enzyme ENTPD5 promotes ATP
consumption and favors aerobic glycolysis.FANG等人在2010年研究出内质网酶ENTPD5能够促进ATP的消耗以及有助于糖的有氧酵解。
The ndings suggest that nutrient uptake in cancer cells is limited by ATP and satis es energy
requirements other than ATP production. 这些发现表明癌细胞中营养的摄取受ATP的限制，可满足ATP产生之外的能量需求。
Mounting evidence suggests that cancer cells engage in a unique metabolic program that allows for rapid cell proliferation. Nonproliferating cells can use glycolysis products to generate ATP for their energy needs. Such cells generally have low rates of glycolysis followed by
oxidation of pyruvate in the mitochondria, leading to ef cient generation of ATP. Dividing cells, in contrast, also use glycolysis intermediates for the synthesis of macromolecules and must therefore balance their ATP requirements and biosynthetic needs (Vander Heiden et al., 2009). Metabolism of glucose by aerobic glycolysis, a phenomenon known as the Warburg effect, may help piding cells strike this balance.
大量证据表明癌细胞处于一个可使细胞快速增殖的独特代谢程序中。非增殖细胞可使用糖酵解产物产生ATP满足自身能量需要。这种细胞一般糖酵解的速度较低，之后通过丙酮酸在线粒体的氧化，有效产生ATP。而正在分裂的细胞也使用糖酵解中间物进行大分子的合成，所以必须对ATP需求和生物合成需求进行平衡。通过有氧糖酵解进行的葡萄糖代谢（瓦伯格效应）可帮助进行分裂的细胞达到这种平衡。
The phosphoinositide 3-kinase (PI3K) signaling pathway, which is activated in many cancers, regulates cell growth and survival. PI3K signaling has been implicated in the altered glucose
metabolism of cancer cells, and the serine/threonine kinase AKT, a major PI3K effector, promotes glucose uptake and increases the activity of glycolytic enzymes (DeBerardinis et al., 2008). In this issue of Cell, Fang et al. (2010) report an important mechanism by which AKT signaling leads to increased aerobic glycolysis. They show that AKT activation promotes protein glycosylation in the endoplasmic reticulum, which elevates ATP consumption and derepresses a rate-limiting enzyme in glycolysis that is otherwise inhibited by an elevated ratio of ATP to AMP. This work suggests how proliferating cells may integrate growth signals with energy status to enable increased glucose uptake to support cell proliferation.
在许多癌症中被激活的磷酸肌醇3激酶(PI3K)信号传导途径调节细胞生长和存活。PI3K信号传导参与癌细胞中改变了的葡萄糖代谢，丝氨酸/苏氨酸激酶AKT是一个主要PI3K作用因子，它促进葡萄糖摄取并增加糖酵解酶的活性。Fang等在本期Cell报道了AKT导致有氧糖酵解增加的一个重要机制。他们表明AKT活化促进内质网中蛋白质的糖基化，从而增加ATP消耗，抑制糖酵解中的限速酶（原本受ATP与ADP比例增加的限制）。这项研究表明增殖中的细胞怎样使生长信号与能量状态整合，增加葡萄糖摄取，支持细胞增殖。
Activation of the PI3K pathway in cancer can occur via genetic alterations that allow growth factor-independent kinase activation or via the loss of PTEN, a lipid phosphatase that attenuates PI3K signaling. Fang et al. now nd that cell extracts from PTEN-de cient cells have an enhanced ability to generate AMP from ATP. Subsequent puri cation and biochemical characterization of this activity led to the identi cation of ectonucleoside triphosphate diphosphohydrolase 5
(ENTPD5) as the enzyme associated with the ATP hydrolysis activity. PI3K signaling leads to upregulation of ENTPD5, a UDPase that promotes the N-glycosylation and folding of
glycoproteins in the ER by hydrolyzing UDP to UMP (Trombetta and Helenius, 1999) (Figure 1). UDP hydrolysis in the ER is a reaction necessary to promote protein folding via the
calnexin/calreticulin pathway. It is linked to ATP hydrolysis in the cytosol by a cycle of glucose and phosphate transfer reactions. As part of this cycle, the UDP-glucose/UMP antiporter exports UMP out of the ER in exchange for importing UDP-glucose into the ER (Hirschberg et al., 1998). The UGGT enzyme then uses UDP-glucose to transfer glucose to proteins in the ER (Vembar and
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Brodsky, 2008). This glucose addition to nascent glycoproteins is necessary for their
calnexin/calreticulin-mediated protein folding. Thus, disruption of ENTPD5 in PTEN-de cient cells results in decreased protein N-glycosylation and causes ER stress.
通过遗传改变使独立于生长因子的激酶活化或通过使减弱PI3K信号传导的脂磷酸酶PTEN丧失，可以在癌细胞中产生PI3K途径的激活。Fang等发现从PTEN缺失细胞中制备的细胞抽提物，从AMP产生ATP的能力提高。之后对这种活性的纯化和生化分析鉴定了外核苷三磷酸双磷酸酶5 (ENTPD5)是与ATP水解活性相关联的酶。PI3K信号传导导致ENTPD5上调，ENTPD5是UDPase，通过水解UDP形成UMP，促进N-糖基化和在ER中的糖蛋白折叠。在ER中UDP的水解是通过钙联接蛋白/钙网蛋白途径促进蛋白质折叠的必要反应。它通过葡萄糖循环和磷酸转移酶的反应，在细胞质中与ATP水解连接。这个循环的一部分是UDP-葡萄糖/UMP逆向转运体从ER输出UMP，与进入ER的UDP-葡萄糖进行交换。之后UGGT酶在ER中使用UDP-葡萄糖将葡萄糖转移到蛋白质分子上。在新生糖蛋白上加入葡萄糖是ER中钙联接蛋白/钙网蛋白介导的蛋白质折叠所必需的。因此在PTEN缺失细胞中破坏ENTPD5可导致蛋白质N糖基化的下降并引起ER应力。
Cell surface proteins, including many growth factor receptors, are N-glycosy-lated. Fang et al. show that disruption of ENTPD5 leads to decreased levels of several growth factor receptors,
including epidermal growth factor receptor (EGFR), insulin-like growth factor receptorb (IGFR-b), and Her2/ErbB2. Given that growth factor signaling plays an important role in increasing nutrient metabolism in rapidly proliferating cells (DeBerardinis et al., 2008), these new ndings suggest that cellular ATP levels can in uence the folding and expression of growth factor receptors, perhaps ensuring that cells do not attempt to grow when ATP is limiting. Furthermore, because glucose metabolism by the hexosamine biosynthesis pathway provides the carbon for these
receptor glycosylation events, the availability of glucose may provide a means to couple nutrient levels with growth factor receptor expression. These feedbacks may exist to prevent a metabolic catastrophe caused by activation of the cell growth machinery when the supply of nutrients or ATP is limiting.
包括许多生长因子受体在内的细胞表面蛋白是N糖基化的。Fang等表明ENTPD5的破坏可导致几种生长因子受体水平的下降，包括上皮生长因子受体(EGFR)、胰岛素类生长因子受体β(IGFR-β)和her2/ErbB2。因为在迅速生长的细胞中，生长因子信号传导在增加营养代谢方面起重要作用，Fang等的新发现表明细胞中ATP的水平可影响生长因子受体的折叠和表达，保证细胞在ATP受到限制时不生长。另外，由于通过氨基己醣生物合成途径进行的葡萄糖代谢为上述受体的糖基化提供碳，因此葡萄糖的存在可为营养水平与生长因子受体表达提供一种偶联方式。这些反馈的存在可在营养供给或ATP受到限制时，避免因细胞生长机制活化引发代谢灾难。
How does ENTPD5 regulate ATP levels? Fang et al. nd that reconstitution of the ATP consuming activity also requires the presence of UMP/CMP kinase-1 and adenylate kinase-1.
UMP/CMP kinase-1 catalyzes the rephosphorylation of the UMP generated by ENTPD5 into UDP (Figure 1), in the process converting ATP to ADP. Adenylate kinase-1 then converts ADP molecules into ATP and AMP, thus allowing the cycle to continue. Surprisingly, this cycle
involving ENTPD5 is a major source of ATP consumption in PTEN-de cient cells. Furthermore, these reactions directly affect the cell’s glycolytic rate. Whereas increased ENTPD5 expression has no effect on cellular respiration, it increases lactate production, suggesting a link between ATP consumption and increased glycolytic ux. In a series of experiments to determine how ENTPD5 increases glucose entry into glycolysis, Fang et al. nd that the ratio of fructose- 6-phosphate to fructose-1-6-bisphosphate increases in cells following ENTPD5 knockdown, consistent with inhibition of this step in glycolysis. Phosphofructokinase (PFK), the enzyme that catalyzes this reaction, is the major enzyme controlling glucose commitment to the glycolytic pathway (Dunaway, 1983). A high ATP/AMP ratio in the cell inhibits both PFK activity and glucose metabolism by glycolysis. In fact, the authors conclude that increased ATP consumption by
ENTPD5 increases glycolysis by lowering the ATP/AMP ratio and relieving allosteric inhibition of PFK.
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ENTPD5怎样调节ATP水平？Fang等发现ATP消耗活性的重建还需要有UMP/CMP激酶1和腺苷酸激酶1的存在。在将ATP转换成ADP的过程中，UMP/CMP激酶1催化由ENTPD5产生的UMP的重新磷酸化，形成UDP（图1）。之后腺苷酸激酶1将ADP转换成ATP和AMP，使循环持续进行。令人惊讶的是，这种有ENTPD5参与的循环是PTEN缺失细胞中ATP消耗的主要途径。另外，这些反应直接影响细胞的糖基化速度。尽管ENTPD5表达的增加对细胞呼吸没有影响，但可增加乳酸产生，表明在ATP消耗和蛋白质糖基化增加之间存在关联。Fang等在一系列测定ENTPD5怎样增加葡萄糖进入酵解的实验中，发现在ENTPD5敲除之后，果糖-6-磷酸与果糖-1，6-二磷酸的比例增加，与在酵解中这个步骤受到抑制的观点一致。催化这个反应的磷酸果糖激酶(PFK)是控制葡萄糖进入酵解途径的主要酶。细胞中高ATP/AMP比例可抑制PFK活性和酵解中葡萄糖代谢。Fang等的结论是。ENPTD5对ATP消耗的增加可降低ATP/AMP比例，解除PFK的变构抑制，从而增加酵解。
ATP is likely not the growth-limiting resource for most cells (Vander Heiden et al., 2009). The concept that glucose utilization by tumor cells may be limited by ATP consumption to prevent feedback inhibition of PFK has been suggested previously (Scholnick et al., 1973). This study nally provides a mechanism by which cells can increase ATP consumption to drive glucose uptake. An additional mechanism has also recently been described in which glucose incorporation into biosynthetic pathways occurs without producing excess ATP (Vander Heiden et al., 2010). Together, these studies support the notion that altered metabolism in cancer is not adapted to support ATP production.
ATP可能并不是大多数细胞的生长限定资源。先前有人提出，ATP消耗可能限制肿瘤细胞利用葡萄糖，阻止PFK的反馈抑制。Fang等人的研究提供了一个细胞通过增加ATP消耗驱动葡萄糖摄取的机制。最近也有人描述了葡萄糖进入生物合成途径，无过量ATP产生的机制。总体上这些研究支持癌症中代谢的改变并不促进ATP产生的观点。
Fang et al. show that ENTPD5 expression correlates with PI3K activation in human prostate cancer cell lines and tumor tissue samples. Not all cancer cells are dependent on activated PI3K, suggesting that increased ENTPD5 activity may not be a universal mechanism for lowering ATP levels in tumors. However, other enzymes involved in regulating nucleotide pools in cells have also been linked to cancer (Hartsough and Steeg, 2000), and there are additional homologs of ENTPD5 whose functions are not well understood. These enzymes may be involved in analogous cycles of ATP consumption, leading to enhanced glucose metabolism in other genetic contexts. Fang等表明在人前列腺癌细胞系和肿瘤组织中，ENTPD5的表达与PI3K的活化有相关性。因为并不是所有的癌细胞都依赖于PI3K的活化，所以对于降低肿瘤中的ATP水平，ENTPD5的活化可能并不是一个普遍机制。但参与调节细胞中核苷酸库的其他酶也与癌症有关，也有其他一些功能尚不清楚的ENTPD5的同源物。这些酶可能参与其他类似的ATP消耗循环，导致在其他遗传途径中葡萄糖代谢的增加。
Fang et al. also show that decreased ENTPD5 expression inhibits tumor growth, possibly via pleiotropic effects involving induction of ER stress and altered glucose metabolism. Consideration of ENTPD5 as a potential therapeutic target in PI3K-driven cancer is interesting given that pharmacological inhibition of ENTPD5 is predicted to decrease tumor ATP consumption. Although counterintuitive, the resulting increase in ATP/AMP ratio might reduce the entry of glucose into glycolysis and starve the cells of precursors necessary for biosynthesis. Successful efforts to target cancer metabolism will likely arise from understanding the feedbacks and
complex regulation that are required for anabolic metabolism. The study by Fang et al. provides new insight by demonstrating that ATP consumption serves to increase glucose ux to satisfy the energetic and biosynthetic demands of a rapidly proliferating cell.
Fang等还表明，ENTPD5表达的下降可通过ER应力的诱导和葡萄糖代谢的改变等多种影响，抑制肿瘤生长。将ENTPD5作为PI3K衍生的癌症的潜在治疗标靶很重要，因为ENTPD5的药理抑制可降低肿瘤ATP的消耗。尽管违反直觉，但由此产生的ATP/AMP比例的增加可减少葡萄糖进入酵解，使生物合成所必需的细胞前体饥饿。成功地作用癌症的代谢途径需要理
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解分解代谢所需要的反馈和复杂调节。Fang等通过证实ATP消耗可增加葡萄糖流量，满足迅速增殖细胞对能量和生物合成的需求，使我们对这方面的理解更加深入。
ACKNOWLEDGMENTS
We thank Brooke Bevis for her help preparing the gure and editing the manuscript.
M.G.V.H. is a consultant to Agios Pharmaceuticals regarding development of compounds targeting cancer metabolism and is a member of its Scienti c Advisory Board.
致谢
我们要感谢Brooke Bevis准备了图和编辑稿件。m g v h是一个研究针对癌症新陈代谢化合物Agios的制药发展的顾问，是科学顾问委员会的成员。
Abstract：Cancer cells engage in a unique metabolic program that allows for rapid cell
proliferation. Nonproliferating cells can use glycolysis products to generate ATP for their energy needs. Such cells generally have low rates of glycolysis followed by oxidation of pyruvate in the mitochondria, leading to ef cient generation of ATP. Dividing cells, in contrast, also use glycolysis intermediates for the synthesis of macromolecules and must therefore balance their ATP requirements and biosynthetic needs. Cancer cells metabolize glucose by aerobic glycolysis, a phenomenon known as the Warburg effect. Fang et al. (2010) show that the endoplasmic reticulum enzyme ENTPD5 promotes ATP consumption and favors aerobic glycolysis. The ndings suggest that nutrient uptake in cancer cells is limited by ATP and satis es energy requirements other than ATP production.
摘要：癌细胞处于一个可使细胞快速增殖的独特代谢程序中。非增殖细胞可使用糖酵解产物产生ATP满足自身能量需要。这种细胞一般糖酵解的速度较低，之后通过丙酮酸在线粒体的氧化，有效产生ATP。而正在分裂的细胞也使用糖酵解中间物进行大分子的合成，所以必须对ATP需求和生物合成需求进行平衡。癌症细胞的代谢是通过糖的有氧酵解来完成的，这个现象称为瓦伯格效应。FANG等人在2010年研究出内质网酶ENTPD5能够促进ATP的消耗以及有助于糖的有氧酵解。这些发现表明癌细胞中营养的摄取受ATP的限制，可满足ATP产生之外的能量需求。
生化的文章,自己对文章做了分析。
生化的文章,自己对文章做了分析。
