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首页> 外文期刊>Nature >SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
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SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance

机译：SHMT2驱动缺血性脑胶质瘤细胞的存活，但对甘氨酸清除率有依赖性

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摘要

Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransfer-ase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules amino-acetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.
机译：癌细胞适应其新陈代谢过程以支持快速增殖，但是在血管微弱的肿瘤微环境中，癌细胞如何改变新陈代谢以促进细胞存活尚不清楚。在这里，我们确定了神经胶质瘤缺血区内脑癌细胞存活中丝氨酸和甘氨酸代谢的关键作用。在人类胶质母细胞瘤中，线粒体丝氨酸羟甲基转移酶（SHMT2）和甘氨酸脱羧酶（GLDC）在坏死灶周围的假性苍白细胞中高度表达。我们发现SHMT2活性限制了丙酮酸激酶（PKM2）的活性并减少了氧的消耗，从而引发了一种新陈代谢状态，赋予血管化程度低的肿瘤区域中的细胞以深远的生存优势。 GLDC抑制会损害具有高SHMT2水平的细胞，因为未被GLDC代谢的过量甘氨酸可转化为有毒分子氨基丙酮和甲基乙二醛。因此，SHMT2是癌细胞适应肿瘤环境所必需的，但也使这些细胞对甘氨酸裂解系统的抑制敏感。

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  • 来源
    《Nature》 |2015年第7547期|363-367|共5页
  • 作者

    Dohoon Kim; Brian P. Fiske; Kivanc Birsoy; Elizaveta Freinkman; Kenjiro Kami; Richard L. Possemato; Yakov Chudnovsky; Michael E. Pacold; Walter W. Chen; Jason R. Cantor; Laura M. Shelton; Dan Y. Gui; Manjae Kwon; Shakti H. Ramkissoon; Keith L. Ligon; Seong Woo Kang; Matija Snuderl; Matthew G. Vander Heiden; David M. Sabatini;

  • 作者单位

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA,Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA;

    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA;

    Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA,Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA;

    Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA,Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

    Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA;

    The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA,Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;

    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA,Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA,Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA;

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  • 入库时间 2022-08-18 02:52:30

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