肿瘤生长的能量代谢特点及其临床应用

肿瘤细胞与人体正常细胞在代谢上有些不同,这主要体现在能量代谢和物质代谢上。肿瘤细胞能量代谢的特点表现在活跃地摄取葡萄糖和谷胺酰胺,进行有氧糖酵解(Warburg效应)。这种看上去很不经济的能量供给方式对肿瘤细胞却是必需的,它既为肿瘤细胞的不断生长提供能量,也为它们提供了生物合成的原料。肿瘤不同的代谢方式既是挑战也是机遇,弄清肿瘤细胞的代谢机制,对肿瘤早期诊断和靶向治疗具有重要意义。     

能量代谢途径相关基因变异与肿瘤细胞适应性进化

肿瘤细胞的快速增殖是一个极其耗能的过程,尽管如此,肿瘤细胞即便在有氧条件下也主要以糖酵解获取能量(有氧糖酵解),这是肿瘤细胞的显著特征之一。这种产能方式转变导致肿瘤细胞内部发生一系列生理变化,为其快速增殖提供能量物质和用于新细胞合成所需的生物大分子,同时为有效适应肿瘤微环境改变奠定基础。该文通过介绍能量代谢相关基因变异研究进展,基于分子进化视角探讨肿瘤细胞中相关基因可能存在的适应性进化遗传印记,为诠释肿瘤细胞能量代谢方式发生转变的可能机制提供新的视角和证据。     

生物能量分析仪在肿瘤细胞生物能量代谢中的应用研究

靶向肿瘤细胞代谢过程中关键调控分子抑制肿瘤细胞生长的研究日益成为热点。目前,研究肿瘤细胞氧化磷酸化和有氧糖酵解主要是应用Clark氧电极法测定细胞氧耗率以及对相关中间代谢物的测定,如乳酸和葡萄糖。但是,这些方法测定的指标相对单一,而且过程繁琐。该文详细介绍了生物能量分析仪在研究肿瘤细胞糖酵解和线粒体氧耗率中的应用,并通过研究肿瘤细胞应用阿霉素及相关药物处理后生物能量代谢的变化,深入探讨了这一方法在研究肿瘤细胞生物能量代谢方面中的优越性。研究结果表明,羰基氰–对–三氟甲氧基本腙(carbonylcyanide p-trifluoro methoxyphenylhydrazone,FCCP)的浓度以及细胞数量对于研究肿瘤细胞的氧耗率十分关键,应用阿霉素能够显著抑制肿瘤细胞的有氧糖酵解和线粒体氧耗率。通过该文的介绍,期望能为肿瘤细胞生物能量代谢研究提供进一步的参考。     

肿瘤细胞能量代谢特点及其意义CSCD

正常细胞代谢所需的能量主要由线粒体氧化磷酸化产生的ATP提供,而肿瘤细胞即便氧供充足也偏好利用增强糖酵解供能。同时,肿瘤细胞对葡萄糖和谷氨酰胺的摄取利用也十分活跃。肿瘤缺氧微环境,癌基因的激活,线粒体功能的抑制以及如炎症、micro RNA等因素共同促成肿瘤细胞糖酵解代谢表型,它不仅为肿瘤细胞提供充足的ATP,还为新肿瘤细胞的构筑提供生物大分子原料,从而利于生长增殖。基于肿瘤能量代谢模式的内在分子机制研究,将揭开靶向肿瘤治疗的新局面。     

肿瘤细胞能量代谢特点及其意义

<正>常细胞代谢所需的能量主要由线粒体氧化磷酸化产生的ATP提供,而肿瘤细胞即便氧供充足也偏好利用增强糖酵解供能。同时,肿瘤细胞对葡萄糖和谷氨酰胺的摄取利用也十分活跃。肿瘤缺氧微环境,癌基因的激活,线粒体功能的抑制以及如炎症、micro RNA等因素共同促成肿瘤细胞糖酵解代谢表型,它不仅为肿瘤细胞提供充足的ATP,还为新肿瘤细胞的构筑提供生物大分子原料,从而利于生长增殖。基于肿瘤能量代谢模式的内在分子机制研究,将揭开靶向肿瘤治疗的新局面。     

缺氧诱导因子HIF-1在肿瘤Warburg效应中作用机制的研究进展

正常状态下人体细胞的能量主要来源于有氧磷酸化,而在肿瘤细胞,其能量主要来源于糖酵解,即使在含有充足氧气的环境中肿瘤细胞依然进行糖酵解,这种现象被称为Warburg效应.在肿瘤细胞中,缺氧诱导因子HIF-1水平的升高与糖酵解活动的增强密切相关,HIF-1上调一系列与糖酵解能量代谢、血管新生、肿瘤细胞存活和红细胞生成相关的基因,从而促进了肿瘤细胞Warburg效应的发生.在肿瘤细胞代谢重编程过程中,丙酮酸激酶M2(PKM2)与HIF-1之间构成一个正反馈过程,而缺氧诱导因子抑制因子1 (FIH-1)能通过抑制HIF-1对重要基因转录因子CPB/p300的招募,来抑制HIF-1的活性.     

雌激素与葡萄糖能量代谢研究进展

雌激素是类固醇激素,有雌素酮、17β-雌二醇、雌三醇3种形式,通过不同形式的雌激素受体发挥功能。雌激素影响细胞葡萄糖能量代谢,包括葡萄糖转运、糖酵解过程、三羧酸循环和氧化磷酸化作用,同时对葡萄糖能量代谢过程中副产物如甲基乙二醛、活性氧等的产生也具有重要影响。在阿尔茨海默病和肿瘤中都存在葡萄糖能量代谢异常的现象。本文针对阿尔茨海默病和肿瘤就雌激素对葡萄糖能量代谢的调节作用进行综述,以期在预防及治疗相关疾病及开发新药过程中提供新思路。     

肿瘤能量代谢：糖酵解还是氧化磷酸化？

正常细胞代谢活动所需要的能量主要由线粒体氧化磷酸化产生的ATP提供。与正常细胞不同,肿瘤细胞糖酵解增强,氧化磷酸化功能降低。长期以来,肿瘤细胞的有氧糖酵解被认为是由于线粒体出现不可逆的损伤。最近有不少研究结果对这一观点提出质疑,认为多数肿瘤的线粒体氧化磷酸化功能是完好的,肿瘤有氧糖酵解的改变被认为是其他多种因素（例如癌基因、肿瘤抑制基因、低氧微环境、mtDNA突变等）综合作用的结果。     

乳酸代谢——肿瘤治疗新靶点

恶性肿瘤严重危害人类健康,其治疗目前主要有手术、放疗和化疗三种方式,但疗效尚无法达到令人满意的程度,因此寻找肿瘤治疗新靶点、实现肿瘤的靶向治疗非常迫切.Warburg效应普遍存在于多种肿瘤中,其重要特征是在氧气充足的条件下,癌细胞的能量代谢仍以糖酵解为主.Warburg效应是糖酵解的典型过程,葡萄糖被大量吸收并通过糖酵解转化为乳酸.糖酵解产物乳酸可以激活癌细胞中许多重要的信号通路,促进癌细胞的存活、侵袭、免疫逃逸、转移和血管生成.因此,靶向乳酸代谢过程及其关键酶可能为肿瘤治疗提供新的靶点.本文对肿瘤细胞代谢方式的改变,乳酸对肿瘤细胞免疫逃逸、肿瘤转移、肿瘤血管生成的影响,以及以乳酸为靶点的肿瘤治疗等方面进行综述.     

Glut1介导的葡萄糖摄取是B细胞急性淋巴细胞白血病合成代谢和抵抗凋亡所必需

<正>在有氧的条件下,许多肿瘤细胞都会利用有氧糖酵解来提供能量和支持细胞生长。这一细胞代谢的转变导致糖酵解的上调和乳酸产生的增加。在有氧糖酵解中探索出限制性的步骤,并通过代谢性手段来抑制肿瘤细胞反应,已经成为代谢性治疗肿瘤的关键问题。在临床中发现,大约1/4患有B细胞急性淋巴细胞白血病的病人中,B细胞中会出现致癌激酶BCR-Abl,这种病人一般预     

An update on therapeutic opportunities offered by cancer glycolytic metabolism

Almost all invasive cancers, regardless of tissue origin, are characterized by specific modifications of their cellular energy metabolism. In fact, a strong predominance of aerobic glycolysis over oxidative phosphorylation (Warburg effect) is usually associated with aggressive tumour phenotypes. This metabolic shift offers a survival advantage to cancer cells, since they may continue to produce energy and anabolites even when they are exposed to either transient or permanent hypoxic conditions. Moreover, it ensures a high production rate of glycolysis intermediates, useful as building blocks for fast cell proliferation of cancer cells. This peculiar metabolic profile may constitute an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. In this review we provide an update about some of the most recent advances in the discovery of new bioactive molecules that are able to interfere with cancer glycolysis.     

Understanding the tumor metabolic phenotype in the genomic era

Now, at the beginning of a new century, 80 years after Warburg's Nobel prize winning discoveries, we are beginning to make sense of the underlying causes of the well known metabolic phenotype of tumor cells. Building on decades of research to understand the interrelationships between respiration and glycolysis in cancer, the tumor metabolic phenotype can now begin to be understood in a genomic context. With the discovery of hypoxia inducible factor-1 (HIF-1), which is widely overexpressed across a broad range of cancers, modern molecular tools have allowed us to put together the pattern of events that might explain the metabolic differences between tumor and normal cells. HIF-1 controls cellular and systemic responses to oxygen availability and coordinates up-regulation of genes involved in many pathways concerned with tumour growth and metabolism including angiogenesis, glucose and energy metabolism, cellular proliferation, differentiation and viability, apoptosis, pH regulation and matrix metabolism. These findings begin to explain how glucose uptake and glycolysis could be up-regulated in cancer cells (through binding to a core DNA recognition sequence) in a co-ordinated and constitutive fashion that may also allow us to elucidate new targets for tumor therapy.     

The metabolic interaction of cancer cells and fibroblasts – coupling between NAD(P)H and FAD,intracellular pH and hydrogen peroxide

Alteration in the cellular energy metabolism is a principal feature of tumors. An important role in modifying cancer cell metabolism belongs to the cancer-associated fibroblasts. However, the regulation of their interaction has been poorly studied to date. In this study we monitored the metabolic status of both cell types by using the optical redox ratio and the fluorescence lifetimes of the metabolic co-factors NAD(P)H and FAD, in addition to the intracellular pH and the hydrogen peroxide levels in the cancer cells, using genetically encoded sensors. In the co-culture of human cervical carcinoma cells HeLa and human fibroblasts we observed a metabolic shift from oxidative phosphorylation toward glycolysis in cancer cells, and from glycolysis toward OXPHOS in fibroblasts, starting from Day 2 of co-culturing. The metabolic switch was accompanied by hydrogen peroxide production and slight acidification of the cytosol in the cancer cells in comparison with that of the corresponding monoculture. Therefore, our HeLa-huFb system demonstrated metabolic behavior similar to Warburg type tumors. To our knowledge, this is the first time that these 3 parameters have been investigated together in a model of tumor-stroma co-evolution. We propose that determination of the start-point of the metabolic alterations and understanding of the mechanisms of their realization can open a new ways for cancer treatment.     

Targeting cellular metabolism to improve cancer therapeutics

The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.     

Proteomics revisits the cancer metabolome

Many cancer cells utilize aerobic glycolysis (also known as the 'Warburg effect'), instead of mitochondrial oxidative phosphorylation, to generate the energy necessary for diverse cellular processes. In tumor cells, mitochondria play more important roles in anabolism, for instance, de novo lipid biosynthesis and glutamine-dependent anaplerosis to fuel robust cell growth and proliferation. Proteomic analysis of tumor-related alterations of metabolism-associated proteins clearly indicates that such metabolic reprogramming contributes to cancer cell survival and cancer progression. Moreover, proteomics-based systems biology provides a powerful tool to re-evaluate the metabolic phenotype and regulatory mechanism associated with malignant cancer cells, and underscores their implications for cancer diagnosis and therapy. This article will address recent exciting advances in the understanding of cancer cell metabolism using proteomics-based systems biology approaches.     

TRPM7 regulates quiescent/proliferative metabolic transitions in lymphocytes

A unique property of lymphocytes among all body tissues is their capacity for rapid proliferation in the context of responding to infectious challenges. Lymphocyte proliferation involves a transition from a quiescent metabolic state adjusted to maintain cellular energy homeostasis, to a proliferative metabolic state in which aerobic glycolysis is used to generate energy and biosynthetic precursors necessary for the accumulation of cell mass. Here we show that modulation of TRPM7 channel function in tumor B lymphocytes directly induces quiescent/proliferative metabolic transitions. As TRPM7 is widely expressed outside of the immune system, our results suggest that TRPM7 may play an active role in regulating metabolic transitions associated with rapid cellular proliferation and malignancy.Key words: aerobic glycolysis, lymphocyte, metabolism, quiescence, TRPM7     

Malate–aspartate shuttle promotes l-lactate oxidation in mitochondria

Metabolism in cancer cells is rewired to generate sufficient energy equivalents and anabolic precursors to support high proliferative activity. Within the context of these competing drives aerobic glycolysis is inefficient for the cancer cellular energy economy. Therefore, many cancer types, including colon cancer, reprogram mitochondria-dependent processes to fulfill their elevated energy demands. Elevated glycolysis underlying the Warburg effect is an established signature of cancer metabolism. However, there are a growing number of studies that show that mitochondria remain highly oxidative under glycolytic conditions. We hypothesized that activities of glycolysis and oxidative phosphorylation are coordinated to maintain redox compartmentalization. We investigated the role of mitochondria-associated malate–aspartate and lactate shuttles in colon cancer cells as potential regulators that couple aerobic glycolysis and oxidative phosphorylation. We demonstrated that the malate–aspartate shuttle exerts control over NAD⁺/NADH homeostasis to maintain activity of mitochondrial lactate dehydrogenase and to enable aerobic oxidation of glycolytic l -lactate in mitochondria. The elevated glycolysis in cancer cells is proposed to be one of the mechanisms acquired to accelerate oxidative phosphorylation.     

Tumor Cells Switch to Mitochondrial Oxidative Phosphorylation under Radiation via mTOR-Mediated Hexokinase II Inhibition - A Warburg-Reversing Effect

A unique feature of cancer cells is to convert glucose into lactate to produce cellular energy, even under the presence of oxygen. Called aerobic glycolysis [The Warburg Effect] it has been extensively studied and the concept of aerobic glycolysis in tumor cells is generally accepted. However, it is not clear if aerobic glycolysis in tumor cells is fixed, or can be reversed, especially under therapeutic stress conditions. Here, we report that mTOR, a critical regulator in cell proliferation, can be relocated to mitochondria, and as a result, enhances oxidative phosphorylation and reduces glycolysis. Three tumor cell lines (breast cancer MCF-7, colon cancer HCT116 and glioblastoma U87) showed a quick relocation of mTOR to mitochondria after irradiation with a single dose 5 Gy, which was companied with decreased lactate production, increased mitochondrial ATP generation and oxygen consumption. Inhibition of mTOR by rapamycin blocked radiation-induced mTOR mitochondrial relocation and the shift of glycolysis to mitochondrial respiration, and reduced the clonogenic survival. In irradiated cells, mTOR formed a complex with Hexokinase II [HK II], a key mitochondrial protein in regulation of glycolysis, causing reduced HK II enzymatic activity. These results support a novel mechanism by which tumor cells can quickly adapt to genotoxic conditions via mTOR-mediated reprogramming of bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative phosphorylation. Such a “waking-up” pathway for mitochondrial bioenergetics demonstrates a flexible feature in the energy metabolism of cancer cells, and may be required for additional cellular energy consumption for damage repair and survival. Thus, the reversible cellular energy metabolisms should be considered in blocking tumor metabolism and may be targeted to sensitize them in anti-cancer therapy.