Abdul-Aziz Amina, MacEwan David J, Bowles Kristian M, Rushworth Stuart A
Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
Oxid Med Cell Longev. 2015;2015:454659. doi: 10.1155/2015/454659. Epub 2015 Mar 30.
Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.
在几乎所有癌症中，包括白血病，都观察到由于活性氧（ROS）水平升高导致的氧化应激，ROS在这些癌症中促进疾病的发展和进展。然而，癌细胞中抗氧化蛋白的表达水平也会增加，这些蛋白可使ROS解毒。这包括谷胱甘肽，它是人类细胞中的主要抗氧化剂，最近已被确定在人类白血病中代谢失调。这表明癌细胞功能、生长和存活需要细胞内ROS水平的关键平衡。核因子（红系衍生2）样2（NRF2）转录因子在癌症中发挥双重作用。首先，NRF2是一种转录因子，通过转录激活解毒和抗氧化酶，起到保护非恶性细胞免于恶性转化和氧化应激的作用。然而，一旦细胞内发生恶性转化，NRF2则起到保护肿瘤免受氧化应激和化疗诱导的细胞毒性的作用。此外，抑制白血病细胞中的NRF2氧化应激途径会使它们对细胞毒性化疗更敏感。我们对人类白血病中NRF2生物学的进一步了解可能会为我们潜在地改善未来癌症治疗提供机制。本综述重点介绍白血病细胞利用NRF2/ROS反应促进其生长和存活的机制。
