Dey Prasenjit, Baddour Joelle, Muller Florian, Wu Chia Chin, Wang Huamin, Liao Wen-Ting, Lan Zangdao, Chen Alina, Gutschner Tony, Kang Yaan, Fleming Jason, Satani Nikunj, Zhao Di, Achreja Abhinav, Yang Lifeng, Lee Jiyoon, Chang Edward, Genovese Giannicola, Viale Andrea, Ying Haoqiang, Draetta Giulio, Maitra Anirban, Wang Y Alan, Nagrath Deepak, DePinho Ronald A
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Nature. 2017 Feb 2;542(7639):119-123. doi: 10.1038/nature21052. Epub 2017 Jan 18.
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 enzyme 2 (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 the conversion of 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 cells deficient in mitochondrial malic enzymes 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 diagnosed with this intractable disease.
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，最显著的是SMAD4，在近三分之一的病例中它会发生纯合缺失。由于邻近管家基因的缺失可导致合成致死，我们试图确定SMAD4位点中代谢基因苹果酸酶2（ME2）的缺失在其同源异构体ME3被靶向时是否会产生癌症特异性的代谢脆弱性。线粒体苹果酸酶（ME2和ME3）是氧化脱羧酶，催化苹果酸转化为丙酮酸，对NADPH再生和活性氧稳态至关重要。在这里，我们表明，ME3的缺失以一种与ME3在ME2缺失的癌细胞中的基本功能一致的方式选择性地杀死ME2缺失的PDAC细胞。从机制上讲，对线粒体苹果酸酶缺陷细胞进行综合代谢组学和分子研究发现，NADPH生成减少，随之产生高水平的活性氧。这些变化激活了AMP活化蛋白激酶（AMPK），AMPK进而直接抑制固醇调节元件结合蛋白1（SREBP1）对其直接靶标的转录，这些靶标包括BCAT2（支链氨基酸转氨酶2）基因。BCAT2催化支链氨基酸的氨基转移到α-酮戊二酸（α-KG），从而再生谷氨酸，谷氨酸部分功能是支持从头合成核苷酸。因此，导致NADPH生成受损的线粒体苹果酸酶缺陷为治疗很大一部分被诊断患有这种难治性疾病的患者提供了一种主要的“合成致死”治疗策略。
