Journal Article

Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer

Wang, Huamin, Chang, Edward, Yang, Lifeng, DePinho, Ronald A., Liao, Wen-Ting, Lan, Zangdao, Lee, Jiyoon, Maitra, Anirban, Muller, Florian, Fleming, Jason, Satani, Nikunj, Achreja, Abhinav, Baddour, Joelle, Chen, Alina, Ying, Haoqiang, Gutschner, Tony, Kang, Yaan, Wang, Y. Alan, Wu, Chia Chin, Genovese, Giannicola, Viale, Andrea, Nagrath, Deepak, Dey, Prasenjit, Zhao, Di, Draetta, Giulio

2017

Overview

Depletion of malic enzyme 3 in pancreatic cancer cells that have a deletion of the gene for malic enzyme 2 selectively kills the cells, suggesting that the enzyme might represent a therapeutic target for this subset of cancers. Gene deletion in pancreatic cancer In pancreatic cancer, a commonly deleted genomic region includes the gene that encodes metabolic malic enzyme 2, ME2. The authors show that pancreatic tumour cells depend on the activity of the other malic enzyme isoform, ME3, for survival. This finding reveals a metabolic collateral vulnerability that may be further explored to develop therapeutic strategies. 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 1 . 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 2 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/555 / 631/67/1504/1713 / Amino acids / Amino Acids, Branched-Chain - metabolism / AMP-Activated Protein Kinases - metabolism / Animals / Apoptosis / Biocatalysis / Biosynthesis / Cancer / Carcinoma, Pancreatic Ductal - enzymology / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - psychology / Carcinoma, Pancreatic Ductal - therapy / Cell growth / Chromosome deletion / Complications and side effects / Enzymes / Gene Deletion / Genetic aspects / Health aspects / Homeostasis / Humanities and Social Sciences / Humans / Ketoglutaric Acids - metabolism / letter / Malate Dehydrogenase - deficiency / Malate Dehydrogenase - genetics / Male / Metabolites / Mice / Minor Histocompatibility Antigens - biosynthesis / Minor Histocompatibility Antigens - genetics / Mitochondria / Mitochondria - enzymology / Mitochondria - pathology / multidisciplinary / NADP - biosynthesis / NADP - metabolism / Pancreatic cancer / Pancreatic Neoplasms - enzymology / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Pancreatic Neoplasms - therapy / Pregnancy Proteins - biosynthesis / Pregnancy Proteins - genetics / Reactive Oxygen Species - metabolism / Risk factors / Science / Sterol Regulatory Element Binding Protein 1 - metabolism / Transaminases - biosynthesis / Transaminases - genetics / Tumors