Verma Ajay
Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):366-78. doi: 10.1097/01.mco.0000232895.28674.79.
Tumor hypoxia induces cancer cell treatment resistance, angiogenesis, invasiveness, and overall poor clinical outcome. Cellular adaptations to hypoxia are largely driven by hypoxia-induced alterations in gene transcription, mRNA translation, and protein stability. This review will summarize recent advances in the understanding of mammalian oxygen-sensing mechanisms in normal and cancerous cells.
Specific molecular candidates have been identified that are involved in the primary sensing of hypoxia or its secondary consequences. Chief amongst these are the iron and 2-oxoglutarate-dependent dioxygenases that hydroxylate the alpha subunits of hypoxia-inducible transcription factors. This oxygen-dependent reaction, which prevents the transcription of many genes, is relieved under hypoxia. Evidence for the regulated expression and decay of the hypoxia-inducible transcription factor hydroxylating enzymes suggests that the sensitivity of transcriptional responses to hypoxia can be dynamically adjusted. Recent results also argue that these hydroxylating enzymes may be able to sense not only oxygen availability, but also the accumulation of bioenergetic intermediates and reactive oxygen species. In cancer cells, changes in these metabolites may accompany hypoxia or may occur independently. Several organellar compartments including plasma membrane, mitochondria and endoplasmic reticulum also appear to contribute to oxygen sensing through the generation of metabolites or through regulation of protein translation.
Oxygen-sensing mechanisms induce prominent clinically relevant changes in cancer cells and tumor biology through the control of gene expression. Significant overlap exists between oxygen-sensing mechanisms and other metabolic and cell stress sensing pathways, which allows nonhypoxic cell stresses to activate hypoxia-inducible responses.
肿瘤缺氧会导致癌细胞产生治疗抗性、血管生成、侵袭性增加以及总体临床预后不良。细胞对缺氧的适应性很大程度上是由缺氧诱导的基因转录、mRNA翻译和蛋白质稳定性改变所驱动的。本综述将总结在正常细胞和癌细胞中对哺乳动物氧感应机制理解的最新进展。
已鉴定出参与缺氧的初级感应或其继发后果的特定分子候选物。其中最主要的是铁和2-氧代戊二酸依赖性双加氧酶，它们可使缺氧诱导转录因子的α亚基羟基化。这种依赖氧的反应会阻止许多基因的转录，在缺氧条件下这种反应会解除。缺氧诱导转录因子羟基化酶的表达调控和降解的证据表明，转录反应对缺氧的敏感性可以动态调节。最近的结果还表明，这些羟基化酶可能不仅能够感知氧的可用性，还能感知生物能中间体和活性氧的积累。在癌细胞中，这些代谢物的变化可能与缺氧同时发生，也可能独立发生。包括质膜、线粒体和内质网在内的几个细胞器区室似乎也通过代谢物的产生或通过蛋白质翻译的调节来促进氧感应。
氧感应机制通过控制基因表达在癌细胞和肿瘤生物学中诱导出显著的临床相关变化。氧感应机制与其他代谢和细胞应激感应途径之间存在显著重叠，这使得非缺氧细胞应激能够激活缺氧诱导反应。
