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Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment

机译：抗氧化剂和癌基因挽救由基质附着丧失引起的代谢缺陷

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Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3)K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation.
机译：正常的上皮细胞需要基质附着才能生存，而肿瘤细胞在其天然细胞外基质（ECM）壁outside之外生存的能力取决于是否获得锚定性。尽管凋亡是消除缺乏适当ECM附着的细胞的最快速机制，但最近的报告表明，当凋亡在基质剥夺的细胞中被抑制时，非凋亡性死亡过程会阻止存活。在这里，我们证明了乳腺上皮细胞从ECM脱落会导致ATP缺乏，这是由于葡萄糖转运的丢失。 ERBB2的过表达通过稳定EGFR和磷脂酰肌醇-3-OH激酶（PI（3）K）的活化来恢复葡萄糖摄取，从而挽救了ATP的缺乏，而这种挽救依赖于通过抗氧化剂生成的戊糖磷酸途径的葡萄糖刺激通量。值得注意的是，我们发现可以通过抗氧化剂治疗来挽救ATP的缺乏，而无需挽救葡萄糖的摄取。发现这种拯救取决于脂肪酸氧化的刺激，脂肪酸氧化被脱离诱导的活性氧（ROS）抑制。这些发现的意义得到了乳腺腔腔内基质剥夺细胞中ROS含量增加的证据的支持，并且抗氧化剂促进了这些细胞的存活并增强了与锚定无关的集落的形成。这些结果显示了基质附着在调节代谢活性中的重要性以及通过ATP生成的抗氧化剂还原在改变的基质环境中细胞存活的意外机制。

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  • 来源
    《Nature》 |2009年第7260期|109-113|共5页
  • 作者

    Zachary T. Schafer; Alexandra R. Grassian; Loling Song; Zhenyang Jiang; Zachary Gerhart-Hines; Hanna Y. Irie; Sizhen Gao; Pere Puigserver; Joan S. Brugge;

  • 作者单位

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, 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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