Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma
Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma
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DOI：
10.1073/pnas.1706617114
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发表时间：
2017-10-24
影响因子：
11.1
通讯作者：
Rabinowitz, Joshua D.
中科院分区：
文献类型：
--
作者：
Ducker, Gregory S.;Ghergurovich, Jonathan M.;Rabinowitz, Joshua D.
丝氨酸羟甲基转移酶（SHMT）将丝氨酸转化为甘氨酸和四氢叶酸结合的一碳单位。叶酸一碳单位支持嘌呤和胸苷的合成，从而促进细胞生长。哺乳动物具有胞质SHMT 1和线粒体SHMT 2，其中线粒体同工酶在癌症中强烈上调。在这里，我们从遗传学上表明，双重SHMT 1/2敲除阻断HCT-116结肠癌肿瘤异种移植物的形成。从抑制植物SHMT的吡唑并吡喃支架构建，我们鉴定了人SHMT 1/2的小分子双重抑制剂（生化IC 50类似于10 nM）。代谢组学和同位素示踪剂研究证明了有效的细胞靶点接合。癌细胞系筛选显示B细胞系对SHMT抑制特别敏感。一碳供体甲酸盐通常从SHMT抑制中拯救细胞，但矛盾的是增加了抑制剂在弥漫性大B细胞淋巴瘤（DLBCL）中的细胞毒性。我们表明，这种影响是植根于缺陷的DLBCL细胞系中的甘氨酸摄取，使他们独特地依赖于SHMT酶活性，以满足甘氨酸的需求。因此，甘氨酸输入缺陷是DLBCL的靶向代谢缺陷。
The enzyme serine hydroxymethyltransferse (SHMT) converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Folate one-carbon units support purine and thymidine synthesis, and thus cell growth. Mammals have both cytosolic SHMT1 and mitochondrial SHMT2, with the mitochondrial isozyme strongly up-regulated in cancer. Here we show genetically that dual SHMT1/2 knockout blocks HCT-116 colon cancer tumor xenograft formation. Building from a pyrazolopyran scaffold that inhibits plant SHMT, we identify small-molecule dual inhibitors of human SHMT1/2 (biochemical IC50 similar to 10 nM). Metabolomics and isotope tracer studies demonstrate effective cellular target engagement. A cancer cell-line screen revealed that B-cell lines are particularly sensitive to SHMT inhibition. The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor's cytotoxicity in diffuse large B-cell lymphoma (DLBCL). We show that this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. Thus, defective glycine import is a targetable metabolic deficiency of DLBCL.