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 cases1. 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 homeostasis2,3. 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)4 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.
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Gene Expression Omnibus
We thank T. Tieu for vector cloning; the MD Anderson core facilities, including K. Dunner Jr for High Resolution Electron Microscopy Facility, Sequencing and Microarray Facility (SMF), Flow Cytometry and Cellular Imaging Core Facility; S. Jiang and Z. Xu for assistance in maintenance of mouse colonies; Z. Lu for discussion; and D. Spring for editing. This study was supported by NCI P01 CA117969 grant (R.A.D.); UT Star award (R.A.D.); CPRIT grant RP140612 (R.A.D.); DOD Postdoctoral research fellowship W81XWH-14-1-0429 (P.D.); MD Anderson Bridge Fund (R.A.D.); St. Louis Ovarian Cancer Awareness Research Grant (D.N.) and Odyssey Fellowships at MD Anderson (D.Z., T.G.). The MD Anderson core facilities are supported by NIH P30 CA16672.
Extended data figures
This table contains the tumor progression data.
About this article
Scientific Reports (2019)