缺氧诱导的肿瘤细胞代谢重编程:超越沃伯格效应。
Hypoxia-induced metabolic shifts in cancer cells: moving beyond the Warburg effect.
机构信息
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
出版信息
Int J Biochem Cell Biol. 2011 Jul;43(7):981-9. doi: 10.1016/j.biocel.2010.08.009. Epub 2010 Aug 24.
Hypoxia has been recognized to play a role in promoting the invasive and metastatic behaviour of cancer cells. Largely via the transcription factor, hypoxia-induced factor 1, hypoxia exerts significant effects on cellular metabolism, with numerous downstream consequences. Energetically there is a significant shift away from oxidative phosphorylation in mitochondria towards glycolysis, a state also involved in the 'Warburg effect'. The proteins involved in mediating the altered metabolic pathways seen in tumour cells thus represent new targets for potential therapeutic intervention. Hypoxia has been associated with the development of aggressive phenotypes in cancer cells, and can be accompanied by changes in carbohydrate and lipid metabolism that impact tumour cell proliferation, adhesion, and angiogenesis. Herein, we examine glycolytic and other less investigated metabolic pathways in relation to cancer and hypoxia, with a focus on emerging tools for large-scale metabolite profiling ('metabolomics'). Metabolomic technologies permit the measurement of a wide range of metabolites in an untargeted manner, however, to date, this technology has been relatively under utilized for studying cellular responses to hypoxia. We detail some of the common experimental approaches employed in metabolomics experiments, including nuclear magnetic resonance and new mass spectrometry-based methods of analysis. Selected examples of the application of these technologies to the study of metabolic alterations brought about by hypoxia are provided, particularly as they relate to energy, carbohydrate, and lipid metabolism. Finally, the potential for therapeutic targeting of metabolic processes activated by hypoxia is presented.
缺氧被认为在促进癌细胞的侵袭和转移行为中发挥作用。主要通过转录因子缺氧诱导因子 1,缺氧对细胞代谢产生重大影响,产生许多下游后果。在能量方面,线粒体中的氧化磷酸化向糖酵解发生显著转移,这种状态也涉及“Warburg 效应”。因此,参与调节肿瘤细胞中改变的代谢途径的蛋白质代表了潜在治疗干预的新靶点。缺氧与癌细胞中侵袭表型的发展有关,并且伴随着碳水化合物和脂质代谢的变化,这些变化影响肿瘤细胞的增殖、黏附和血管生成。在此,我们研究了与癌症和缺氧有关的糖酵解和其他研究较少的代谢途径,重点是新兴的大规模代谢物分析工具(代谢组学)。代谢组学技术可以以非靶向的方式测量广泛的代谢物,然而,迄今为止,该技术在研究细胞对缺氧的反应方面相对利用不足。我们详细介绍了代谢组学实验中常用的一些实验方法,包括核磁共振和新的基于质谱的分析方法。提供了这些技术在研究缺氧引起的代谢改变方面的应用的一些示例,特别是与能量、碳水化合物和脂质代谢有关的示例。最后,提出了针对缺氧激活的代谢过程进行治疗靶向的潜力。