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首页> 外文期刊>Nature >Reductive carboxylation supports redox homeostasis during anchorage-independent growth
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Reductive carboxylation supports redox homeostasis during anchorage-independent growth

机译：还原性羧化在锚定非依赖性生长过程中支持氧化还原稳态

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摘要

Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM)(1). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells(2). Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism(2). Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.
机译：细胞通过附着于细胞外基质（ECM）（1）来接受生长和存活刺激。锚定非依赖性生长是大多数恶性细胞的特性，它需要克服ECM诱导的信号上瘾（2）。由于葡萄糖代谢的改变，与ECM的分离与活性氧（ROS）的产生增加有关（2）。在这里，我们确定了一种非常规途径，该途径在适应锚固性独立过程中支持氧化还原稳态和生长。我们观察到，脱离单层培养和生长而成为不依赖于锚定的肿瘤球体，同时伴随着葡萄糖和谷氨酰胺代谢的变化。具体而言，两种营养素在球体中的氧化均得到抑制，而谷氨酰胺还原柠檬酸盐的形成得到增强。还原型谷氨酰胺代谢高度依赖于胞质异柠檬酸脱氢酶-1（IDH1），因为该活性在纯合IDH1无效或经IDH1抑制剂处理的细胞中受到抑制。该活性在缺氧的情况下发生，缺氧是众所周知的还原代谢诱导剂。而是，IDH1减轻了球体中的线粒体ROS，而抑制IDH1通过需要线粒体ROS的机制降低了球体的生长。同位素示踪显示，在球体中，胞浆中还原生成的异柠檬酸盐/柠檬酸盐可进入线粒体并参与氧化代谢，包括IDH2的氧化。这会在线粒体中产生NADPH，从而使细胞减轻线粒体ROS并使生长最大化。 IDH1和IDH2都不是单层生长所必需的，但删除一种增强的线粒体ROS和减小球体大小，以及删除线粒体柠檬酸转运蛋白。总之，数据表明适应锚固性独立性需要柠檬酸盐代谢发生根本变化，这是由依赖IDH1的还原性羧化作用引发的，最终导致线粒体ROS的抑制。

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  • 来源
    《Nature》 |2016年第7598期|255-258|共4页
  • 作者

    Jiang Lei; Shestov Alexander A.; Swain Pamela; Yang Chendong; Parker Seth J.; Wang Qiong A.; Terada Lance S.; Adams Nicholas D.; McCabe Michael T.; Pietrak Beth; Schmidt Stan; Metallo Christian M.; Dranka Brian P.; Schwartz Benjamin; DeBerardinis Ralph J.;

  • 作者单位

    Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA;

    Univ Penn, Sch Med, Dept Radiol, 3620 Hamilton Walk, Philadelphia, PA 19104 USA;

    Seahorse Biosci, 16 Esquire Rd, North Billerica, MA 01862 USA;

    Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA;

    Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA;

    Univ Texas SW Med Ctr Dallas, Touchstone Diabet Ctr, Dallas, TX 75390 USA;

    Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA;

    GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA;

    GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA;

    GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA;

    GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA;

    Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA;

    Seahorse Biosci, 16 Esquire Rd, North Billerica, MA 01862 USA;

    GlaxoSmithKline, 1250 South Collegeville Rd, Collegeville, PA 19426 USA;

    Univ Texas SW Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA|Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA|Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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