Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.
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DOI：
10.1038/nature21052
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发表时间：
2017-02-02
期刊：
影响因子：
64.8
通讯作者：
DePinho RA
中科院分区：
文献类型：
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作者：
Dey P;Baddour J;Muller F;Wu CC;Wang H;Liao WT;Lan Z;Chen A;Gutschner T;Kang Y;Fleming J;Satani N;Zhao D;Achreja A;Yang L;Lee J;Chang E;Genovese G;Viale A;Ying H;Draetta G;Maitra A;Wang YA;Nagrath D;DePinho RA
胰腺导管腺癌（PDAC）的基因组经常包含肿瘤抑制基因位点的缺失，最明显的是SMAD 4，在近三分之一的病例中是同源缺失的。由于邻近管家基因的丢失可以赋予附带致死性，我们试图确定SMAD 4基因座中代谢基因苹果酸酶2（ME 2）的丢失是否会在靶向其旁系同源同种型ME 3时产生癌症特异性代谢脆弱性。线粒体苹果酸酶（ME 2和ME 3）是催化苹果酸至丙酮酸的氧化脱羧酶，并且对于NADPH再生和活性氧物种体内平衡是必需的。在这里，我们表明，ME 3消耗选择性地杀死ME 2无效PDAC细胞的方式与ME 3在ME 2无效癌细胞中的基本功能一致。机械，线粒体苹果酸酶缺陷细胞的综合代谢组学和分子研究显示减少NADPH的生产和随之而来的高水平的活性氧。这些变化激活AMP活化蛋白激酶（AMPK），其进而直接抑制固醇调节元件结合蛋白1（SREBP 1）指导的其直接靶标（包括BCAT 2（支链氨基酸转氨酶2）基因）的转录。BCAT 2催化氨基从支链氨基酸转移至α-酮戊二酸（α-KG），从而再生谷氨酸，谷氨酸的部分功能是支持核苷酸从头合成。因此，线粒体苹果酸酶缺乏症，这导致受损的NADPH生产，提供了一个主要的“附带致死”的治疗策略，用于治疗相当一部分的患者患有这种难治性疾病。
The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of tumour suppressor gene loci, most notably SMAD4, which is homozygously deleted in nearly one-third of cases. As loss of neighbouring housekeeping genes can confer collateral lethality, we sought to determine whether loss of the metabolic gene malic enzyme2 (ME2) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3. The mitochondrial malic enzymes (ME2 and ME3) are oxidative decarboxylases that catalyse malate to pyruvate and are essential for NADPH regeneration and reactive oxygen species homeostasis. Here we show that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of mitochondrial malic enzyme-deficient cells revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP activated protein kinase (AMPK), which in turn directly suppresses sterol regulatory element-binding protein 1 (SREBP1)-directed transcription of its direct targets including the BCAT2 (branched chain amino acid transaminase 2) gene. BCAT2 catalyses the transfer of the amino group from branched chain amino acids to α-ketoglutarate (α–KG)thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime ‘collateral lethality’ therapeutic strategy for the treatment of a substantial fraction of patients suffering from this intractable disease.