Metabolic changes in cancer: beyond the Warburg effect Weihua Wu and Shimin Zhao Acta Biochim Biophys Sin (Shanghai) . 2013 Jan;45(1):18-26. doi: 10.1093/abbs/gms104 School of Life Sciences, Fudan University, Shanghai 200032, China Altered metabolism is one of the hallmarks of cancer cells. The best-known metabolic abnormality in cancer cells is the Warburg effect, which demonstrates an increased glycolysis even in the presence of oxygen. However, tumor-related metabolic abnormalities are not limited to altered balance between glucose fermentation and oxidative phosphorylation. Key tumor genes such as p53 and c-myc are found to be master regulators of metabolism. Metabolic enzymes such as succinate dehydrogenase, fumarate hydratase, pyruvate kinase, and isocitrate dehydrogenase mutations or expressing level alterations are all linked to tumorigenesis. In this review, we introduce some of the cancer-associated metabolic disorders and current understanding of their molecular tumorigenic mechanisms. 图例: PKM2和信号通路间的相互作用 全文: http://abbs.oxfordjournals.org/content/45/1/18.full
Dual roles of PKM2 in cancer metabolism Songfang Wu and Huangying Le Acta Biochim Biophys Sin (Shanghai). 2013 Jan;45(1):27-35. doi: 10.1093/abbs/gms106 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China Cancer cells have distinct metabolism that highly depends on glycolysis instead of mitochondrial oxidative phosphorylation alone, known as aerobic glycolysis. Pyruvate kinase (PK), which catalyzes the final step of glycolysis, has emerged as a potential regulator of this metabolic phenotype. Expression of PK type M2 ( PKM2 ) is increased and facilitates lactate production in cancer cells, which determines whether the glucose carbons are degraded to pyruvate and lactate or are channeled into synthetic processes. Modulation of PKM2 catalytic activity also regulates the synthesis of DNA and lipids that are required for cell proliferation. However, the mechanisms by which PKM2 coordinates high-energy requirements with high anabolic activities to support cancer cell proliferation are still not completely understood. This review summarizes the biological characteristics of PKM2 and discusses the dual role in cancer metabolism as well as the potential therapeutic applications. Given its pleiotropic effects on cancer biology, PKM2 represents an attractive target for cancer therapy. 图例: 细胞代谢通路 全文: http://abbs.oxfordjournals.org/content/45/1/27.full 引用本文的文献: 1 Overexpression of MicroRNA-122 Re-sensitizes 5-FU-Resistant Colon Cancer Cells to 5-FU Through the Inhibition of PKM2 In Vitro and In Vivo 2 Estradiol-17 beta Upregulates Pyruvate Kinase M2 Expression to Coactivate Estrogen Receptor-alpha and to Integrate Metabolic Reprogramming With the Mitogenic Response in Endometrial Cells 3 HSP40 Interacts with Pyruvate Kinase M2 and Regulates Glycolysis and Cell Proliferation in Tumor Cells 4 Reciprocal Regulation of MicroRNA-122 and c-Myc in Hepatocellular Cancer: Role of E2F1 and Transcription Factor Dimerization Partner 2 5 Tumor glycolysis as a target for cancer therapy: progress and prospects 6 Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma
SIRT1 and energy metabolism Xiaoling Li Acta Biochim Biophys Sin (Shanghai). 2013 Jan;45(1):51-60. doi: 10.1093/abbs/gms108 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA Sirtuin 1 (SIRT1) is the most conserved mammalian NAD+-dependent protein deacetylase that has emerged as a key metabolic sensor in various metabolic tissues. In response to different environmental stimuli, SIRT1 directly links the cellular metabolic status to the chromatin structure and the regulation of gene expression, thereby modulating a variety of cellular processes such as energy metabolism and stress response. Recent studies have shown that SIRT1 controls both glucose and lipid metabolism in the liver, promotes fat mobilization and stimulates brown remodeling of the white fat in white adipose tissue, controls insulin secretion in the pancreas, senses nutrient availability in the hypothalamus, influences obesity-induced inflammation in macrophages, and modulates the activity of circadian clock in metabolic tissues. This review focuses on the role of SIRT1 in regulating energy metabolism at different metabolic tissues. 图例: SIRT1是多种组织的重要的代谢调节因子 引用此文的文献: 1 GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity 2 SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation 3 Melatonin reduces endoplasmic reticulum stress and preserves sirtuin 1 expression in neuronal cells of newborn rats after hypoxia-ischemia 4 Defective metabolism in polycystic kidney disease: potential for therapy and open questions 5 Sirtuins: guardians of mammalian healthspan 6 Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways 7 Intestine-Specific Deletion of SIRT1 in Mice Impairs DCoH2-HNF-1 alpha-FXR Signaling and Alters Systemic Bile Acid Homeostasis 8 Small-Molecule Allosteric Activators of Sirtuins 9 Functional Complementation of sir2 Delta Yeast Mutation by the Human Orthologous Gene SIRT1 10 Histone deacetylases and their role in motor neuron degeneration 11 Breed difference of porcine Sirtuin 1, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) 12 SIRT1 Expression Is Associated with the Chemotherapy Response and Prognosis of Patients with Advanced NSCLC 13 Scientific evidence for traditional claim of anti-obesity activity of Tecomella undulata bark 全文: http://abbs.oxfordjournals.org/content/45/1/51.full
英国一项最新研究显示，人体肠道细菌状况的不同可导致人体对药物的反应不同，因此可以通过检测尿液等人体代谢物的成分预测人体对某些药物是否具有不良反应，从而降低服药风险。 英国帝国理工学院等机构研究人员日前报告说，他们以99名年龄在18岁到64岁之间的健康男性志愿者为研究对象，让他们服用常用止痛药“扑热息痛”，并在服药前检测了他们的尿液成分。结果发现，尿液中一种含硫化合物含量不同，志愿者服药后的反应也会不同。 分析显示，这是因为这种含硫化合物是由肠道细菌产生的，而人体同时也需要硫元素来处理“扑热息痛”一类的药物。某些人体内的相关肠道细菌如果功能太强，就会大量消耗硫元素，结果其尿液中含硫化合物含量会较高，而同时人体对药物反应不好。 研究人员说，由于人体使用硫元素来处理包括“扑热息痛”在内的许多药物，因此这一发现有较广泛的应用前景，在实际医疗中可用于降低服药风险。这一研究结果还表明，可以通过改变人体内的细菌状况来改善服药的效果。 相关研究报告发表在新一期美国《国家科学院学报》上。（ 生物谷 Bioon.com） PNAS August 10, 2009, doi: 10.1073/pnas.0904489106 Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism T. Andrew Claytona, David Bakerb, John C. Lindona, Jeremy R. Everettc and Jeremy K. Nicholsona,1 aBiomolecular Medicine, SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom; bPfizer Inc., 50 Pequot Avenue, New London, CT 06320; and cPfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype , in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by 1H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.
前段时间听了一个关于癌症代谢（ Cancer Metabolism ）的报告，其中一位演讲者是 Craig Thompson 。如果用他的名字加上 Cancer 进行搜索，前几条信息中会告诉你两件事：第一、他是纽约的 Memorial Sloan-Kettering Cancer Center 的新科主席。这个癌症研究所的综合水平最近几年稳居 美国癌症研究所排名榜的第一位；第二、他被前任科研单位，附属于宾州大学的 Abramson Family Cancer Research Institute ，告上了法庭，说他把属于研究所的成果带到了他自己开的公司里。 德国科学家 Otto Heinrich Warburg 因为研究线粒体呼吸链而获得诺贝尔奖，他在 1924 年还提出了一个发现：癌症细胞与正常细胞的代谢途径不一样，癌细胞主要通过糖酵解（ Glycolysis ）来代谢葡萄糖，而正常细胞则主要用线粒体呼吸链（ Oxidative Phosphorylation ）代谢葡萄糖。这个发现被称为 Warburg effect 。但在很长的时间里，这个发现没有引起癌症领域的科研工作者的注意。 Craig Thompson 是最早重拾 Warburg effect 并进行深入研究的科学家之一。这个领域目前进展很快，也给大家带来很多希望和遐想。因为癌症治疗最困难的地方是如何把癌细胞与正常细胞区分出来，如果能通过代谢途径的不同，制备出特异杀死癌细胞的药物，那对癌症患者来说，肯定是莫大的福音。 现在 Craig Thompson 的公司还没有研发出可以进入临场的药物，已经得到了两亿六千万美元的资金。这样，他当然可以脱离学校，自己单干了。但学校说，你是从我们这儿起步的，现在快结果子了，你连果带树一起挪走，那也太不地道了。
骨骼肌与代谢——“马拉松小鼠” 在一些耐力项目训练中，经常采用长时间有氧训练，如长跑及自行车项目偶尔建议运动员在空腹状态下训练，或者是选择摄取小量的食物或忽略早餐，以最大程度动员脂肪酸氧化供能。这种建议的可行性如何？以及潜在的机制是什么？ 我们知道骨骼肌存在无氧供能系统和有氧供能系统。不同的运动强度下，不同类型骨骼肌纤维依赖不同的能源物质供能。葡萄糖主要满足 IIa 肌纤维（快肌纤维）的能量供应，慢肌纤维（ I 型肌纤维）更多的是依靠脂肪酸代谢供能。在亚极量耐力运动主要 I 型肌纤维参与供能，表明提高脂肪酸的氧化供能是具有潜在的提高运动能力作用。 肌细胞内甘油三酯，血浆脂蛋白中甘油三酯以及游离脂肪酸是 I 型肌纤维可以利用的脂肪酸来源。实际上，长期耐力训练的运动员骨骼肌积累更多的脂肪，当在空腹状态下，会动用更多的脂肪酸氧化供能。 在空腹或糖原耗竭状态下，运动训练具有潜在的调节 I 型肌纤维代谢。一些研究表明，持续训练引起的肌糖原耗竭，促进骨骼肌参与脂代谢的酶活性提高，脂肪酸转运蛋白及相关基因的表达等，从而有利于线粒体氧化脂肪酸的能力。有趣的是，运动利用碳水化合物耗竭训练方案也提高了运动后再合成肌糖原的能力。这一点 对运动训练是有帮助的，当碳水化合物时在比赛中消耗时，也有助于节约糖原。 最有趣的一项研究，利用转基因小鼠对核转录因子过氧化物酶体增殖物激活受体（ PPAR ）δ的活性形式。研究发现比野生型小鼠耐力提高 2 倍之多，被称为 “马拉松老鼠“。 PPAR δ ，也称为 PPAR β，是 PPAR 受体中研究较少的一种亚型，其主要表达在肌肉组织，被认为能提高线粒体中脂肪酸的氧化供能，尤其中 I 型肌纤维中高表达。通过转基因技术针对性的使该转录因子过度表达，导致肌肉纤维更多地转换成 I 型表型，从而促进脂肪酸的氧化供能。此外，野生型小鼠通过 PPAR δ激动剂治疗与转基因小鼠达到同样的效果。 同禁食的效果一样，耐力训练也提高小鼠及人体骨骼肌 PPARδ 的表达，引起脂肪酸氧化率提高，至少对于提高耐力训练及代谢综合症的患者具有潜在的作用。目前 PPARα 和 PPARγ 激动剂已经用于治疗高血脂及胰岛素抵抗患者。另外有趣的发现是，与野生型相比，“马拉松小鼠”对高脂诱导的肥胖有抵抗作用。鉴于 PPARδ 能诱导 I 型肌纤维的表型和提高脂肪酸的氧化，在药理方面具有可以作为一种“运动药丸”，达到耐力训练的作用，提高代谢效率。 这项研究可能会引领“运动药丸”的研发，让许多患者无须汗流浃背，也可享受运动的益处。 主要参考文献 1. De Bock K, Derave W, Eijnde BO, Hesselink MK, Koninckx E, Rose AJ, Schrauwen P, Bonen A, Richter EA, Hespel P. Effect of training in the fasted state on metabolic responses during exercise with carbohydrate intake. J Appl Physiol. 2008 Apr;104:1045-55. 2. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham J, Kang H, Evans RM. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2004 Oct;2:e294. 3. Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev. 2009 Sep;61:373-93. 4.van Loon LJ, Koopman R, Manders R, van der Weegen W, van Kranenburg GP, Keizer HA. Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes. Am J Physiol Endocrinol Metab. 2004 Sep;287:E558-65. 5.Van Proeyen K, Szlufcik K, Nielens H, Ramaekers M, Hespel P. Beneficial metabolic adaptations due to endurance exercise training in the fasted state. J Appl Physiol.Jan;110:236-45.
一般而言，某种生物的体温每下降 10 摄氏度，其代谢活动会减少约 50% 。然而，美国研究人员 2 月 17 日公布的最新发现表明，尽管阿拉斯加黑熊冬眠时体温只下降 5 到 6 摄氏度，其代谢活动却急剧下降，只有正常水平的 25% 。 阿拉斯加大学费尔班克斯分校及斯坦福大学研究人员监控了部分黑熊 5 个月的冬眠时间，他们观察到，这些熊的体温缓慢地以 2 到 7 天为周期在 30 至 36 摄氏度之间波动。这种现象从未在较小的冬眠动物中发现，而且研究人员此前也根本不知道在哺乳动物中存在这种情况。 通过测量黑熊在模拟巢穴中冬眠时的氧气消耗量，研究人员发现，这些黑熊的代谢活动比夏天时的水平低 75% ，其心率也会从每分钟 55 跳减缓至 14 跳。此外，研究人员还发现，这些黑熊冬眠结束之初，其代谢活动仍然只有正常水平的一半， 2 到 3 周后才完全恢复正常水平。 这项研究成果发表在新一期美国《科学》杂志上。 研究人员表示，黑熊冬眠醒来时，其肌肉、骨质等都完好，功能都没有丧失，如果能够发现黑熊这一本领的遗传学奥秘以及降低代谢需要的机制，就有可能开发出新的治疗方法和药物，用于预防骨质疏松、废用性肌萎缩，甚至可将受伤者置放到某种活动力暂停或降低的状态，直到他们能接受先进医疗护理，即把抢救治疗的黄金小时延长为黄金日或黄金周。（来源：新华网任海军） Science 18 February 2011: Vol. 331 no. 6019 pp. 906-909 Hibernation in Black Bears: Independence of Metabolic Suppression from Body Temperature ivind Tien 1 , * , John Blake 1 , Dale M. Edgar 2 , † , Dennis A. Grahn 3 , H. Craig Heller 3 , and Brian M. Barnes 1 , * Author Affiliations 1 Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK 99775, USA. 2 Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, CA 94305, USA. 3 Department of Biological Sciences, Stanford University, CA 94305, USA. Author Notes * To whom correspondence should be addressed. E-mail: otoien@alaska.edu (O.T.); bmbarnes@alaska.edu (B.M.B.) † Present address: Lilly Research Centre, Eli Lilly, Windlesham, Surrey, GU20 6PH, UK. Abstract Black bears hibernate for 5 to 7 months a year and, during this time, do not eat, drink, urinate, or defecate. We measured metabolic rate and body temperature in hibernating black bears and found that they suppress metabolism to 25% of basal rates while regulating body temperature from 30° to 36°C, in multiday cycles. Heart rates were reduced from 55 to as few as 9 beats per minute, with profound sinus arrhythmia. After returning to normal body temperature and emerging from dens, bears maintained a reduced metabolic rate for up to 3 weeks. The pronounced reduction and delayed recovery of metabolic rate in hibernating bears suggest that the majority of metabolic suppression during hibernation is independent of lowered body temperature.
标签: 代谢
