丝氨酸羟甲基转移酶2（SHMT2）在缺血状态下驱动胶质瘤细胞存活，但使细胞对甘氨酸清除产生依赖。
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.
作者信息
Kim Dohoon, Fiske Brian P, Birsoy Kivanc, Freinkman Elizaveta, Kami Kenjiro, Possemato Richard L, Chudnovsky Yakov, Pacold Michael E, Chen Walter W, Cantor Jason R, Shelton Laura M, Gui Dan Y, Kwon Manjae, Ramkissoon Shakti H, Ligon Keith L, Kang Seong Woo, Snuderl Matija, Vander Heiden Matthew G, Sabatini David M
机构信息
1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
出版信息
Nature. 2015 Apr 16;520(7547):363-7. doi: 10.1038/nature14363. Epub 2015 Apr 8.
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 hydroxymethyltransferase (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 aminoacetone 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.
癌细胞会调整其代谢过程以支持快速增殖，但对于癌细胞如何改变代谢以在血管化不良的肿瘤微环境中促进细胞存活，人们了解得较少。在这里，我们确定了丝氨酸和甘氨酸代谢在胶质瘤缺血区域内脑癌细胞存活中的关键作用。在多形性胶质母细胞瘤中，线粒体丝氨酸羟甲基转移酶（SHMT2）和甘氨酸脱羧酶（GLDC）在围绕坏死灶的假栅栏状细胞中高度表达。我们发现，SHMT2活性限制了丙酮酸激酶（PKM2）的活性并减少了氧气消耗，引发了一种代谢状态，赋予血管化不良肿瘤区域中的细胞显著的生存优势。GLDC抑制会损害SHMT2水平高的细胞，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抑制敏感。
Zotero 插件