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首页> 外文期刊>Cell metabolism >Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment
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Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

机译：Keap1 / NRF2和PI3K途径之间的协同作用将非小细胞肺癌与改变的免疫微环境驱动

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摘要

The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1(f/f)/Pten(f/f) tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations.
机译：肺呈现出高度氧化的环境，通过参与严格控制的应激反应途径可以耐受。一个关键的应激反应介质是转录因子核因子红系-2相关因子2（NFE2L2/NRF2），它由Kelch样ECH相关蛋白1（KEAP1）负调控。在23%的肺腺癌中已发现KEAP1/NRF2通路的改变，这表明该通路的去调控是主要的癌症驱动因素。我们证明小鼠肺中Keap1和Pten的失活促进腺癌的形成。值得注意的是，Keap1（f/f）/Pten（f/f）荷瘤小鼠血浆中鉴定的代谢物表明，肿瘤的发生与戊糖磷酸途径的重新编程有关。此外，Keap1和Pten缺失显著改变了免疫环境，利用免疫检查点抑制实现了肿瘤消退。因此，我们的研究强调了利用代谢和免疫特性检测和治疗含有KEAP1/NRF2通路改变的肺肿瘤的能力。

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  • 来源
    《Cell metabolism》 |2018年第4期|共13页
  • 作者

    Best Sarah A.; De Souza David P.; Kersbergen Ariena; Policheni Antonia N.; Dayalan Saravanan; Tull Dedreia; Rathi Vivek; Gray Daniel H.; Ritchie Matthew E.; McConville Malcolm J.; Sutherland Kate D.;

  • 作者单位

    Walter &

    Eliza Hall Inst Med Res ACRF Stem Cells &

    Canc Div Parkville Vic 3052 Australia;

    Metabol Australia Mol Sci &

    Biotechnol Inst Bio21 Parkville Vic 3052 Australia;

    Walter &

    Eliza Hall Inst Med Res ACRF Stem Cells &

    Canc Div Parkville Vic 3052 Australia;

    Univ Melbourne Dept Med Biol Parkville Vic 3052 Australia;

    Metabol Australia Mol Sci &

    Biotechnol Inst Bio21 Parkville Vic 3052 Australia;

    Metabol Australia Mol Sci &

    Biotechnol Inst Bio21 Parkville Vic 3052 Australia;

    Univ Melbourne St Vincents Hosp Dept Anat Pathol Fitzroy Vic 3065 Australia;

    Univ Melbourne Dept Med Biol Parkville Vic 3052 Australia;

    Univ Melbourne Dept Med Biol Parkville Vic 3052 Australia;

    Metabol Australia Mol Sci &

    Biotechnol Inst Bio21 Parkville Vic 3052 Australia;

    Walter &

    Eliza Hall Inst Med Res ACRF Stem Cells &

    Canc Div Parkville Vic 3052 Australia;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 内分泌腺疾病及代谢病;
  • 关键词

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