文章：

癌细胞代谢的调节

Regulation of cancer cell metabolism

原文发布日期：2011-01-24

DOI: 10.1038/nrc2981

类型: Review Article

开放获取: 否

要点：

1. Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells: rapid ATP generation to maintain energy status; increased biosynthesis of macromolecules; and tightened maintenance of appropriate cellular redox status. Metabolic changes are a common feature of cancerous tissues, although it is unclear to what extent these metabolic changes are important in low-grade slow growing tumours.
2. The best characterized metabolic phenotype observed in tumour cells is the Warburg effect, which is a shift from ATP generation through oxidative phosphorylation to ATP generation through glycolysis, even under normal oxygen concentrations. This effect is regulated by the PI3K, hypoxia-indicible factor (HIF), p53, MYC and AMP-activated protein kinase (AMPK)–liver kinase B1 (LKB1) pathways.
3. Metabolic adaptation in tumours extends beyond the Warburg effect. It is becoming clear that alterations to metabolism balance the need of the cell for energy with its equally important need for macromolecular building blocks and maintenance of redox balance. To this end, a key molecule produced as a result of altered cancer metabolism is reduced nicotinamide adenine dinucleotide phosphate (NADPH), which functions as a cofactor and provides reducing power in many enzymatic reactions that are crucial for macromolecular biosynthesis. NADPH is also an antioxidant and forms part of the defence against reactive oxygen species (ROS) that are produced during rapid proliferation.
4. High levels of ROS can cause damage to macromolecules, which can induce senescence and apoptosis. Cells counteract the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX). Several of these antioxidant systems, including GSH and TRX, rely on the reducing power of NADPH to maintain their activities.
5. In addition to the genetic changes that alter tumour cell metabolism, the abnormal tumour microenvironment — such as hypoxia, pH and low glucose concentrations — have a major role in determining the metabolic phenotype of tumour cells.
6. Mutations in oncogenes and tumour suppressor genes cause alterations to multiple intracellular signalling pathways that affect tumour cell metabolism and re-engineer it to allow enhanced survival and growth.

要点翻译：

1. 多种分子机制，包括内在与外在机制，共同改变核心细胞代谢，以满足分裂细胞的三个基本需求：快速生成ATP以维持能量状态；增加大分子的生物合成；以及加强维持适宜的细胞氧化还原状态。代谢变化是癌组织的共同特征，尽管目前尚不清楚这些代谢变化在低级别缓慢生长的肿瘤中的重要程度。
2. 肿瘤细胞中最具特征性的代谢表型是瓦伯格效应，即即使在正常氧浓度下，细胞也从通过氧化磷酸化生成ATP转变为通过糖酵解生成ATP。这一效应受PI3K、缺氧诱导因子（HIF）、p53、MYC和AMP激活蛋白激酶（AMPK）–肝激酶B1（LKB1）通路调控。
3. 肿瘤的代谢适应不仅限于瓦伯格效应。越来越明确的是，代谢的改变平衡了细胞对能量的需求与其对大分子构建模块和氧化还原平衡维持的同等重要需求。为此，癌症代谢改变产生的一个关键分子是还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH），它作为辅因子，在为巨分子生物合成关键的许多酶反应中提供还原力。NADPH也是一种抗氧化剂，并构成防御在快速增殖过程中产生的活性氧（ROS）的一部分。
4. 高水平的ROS会对大分子造成损害，从而诱导衰老和凋亡。细胞通过产生抗氧化分子，如还原型谷胱甘肽（GSH）和硫氧还蛋白（TRX），来抵消ROS的有害影响。这些抗氧化系统中的几种，包括GSH和TRX，依赖NADPH的还原力来维持其活性。
5. 除了改变肿瘤细胞代谢的遗传变化外，异常的肿瘤微环境——如缺氧、pH值和低葡萄糖浓度——在决定肿瘤细胞的代谢表型中也起着重要作用。
6. 癌基因和肿瘤抑制基因的突变导致多种细胞内信号通路的改变，这些通路影响肿瘤细胞代谢并重新编程代谢，以增强生存和生长能力。

英文摘要：

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

摘要翻译： 

肿瘤代谢这一话题在一个世纪的癌症研究中几经沉浮。Warburg及其同时代学者的早期观察确立了恶性组织中运行的核心代谢通路存在根本性差异。然而，基于这些观察提出的初始假说并无力解释肿瘤发生，随着癌基因革命的兴起，肿瘤代谢被推向癌症研究的边缘。近年来，人们重新燃起兴趣，因为已显而易见：受基因突变和肿瘤微环境影响的众多信号通路对核心代谢产生深远影响，使该领域再度成为癌症生物学研究最火热的方向之一。

原文链接：

Regulation of cancer cell metabolism