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

Abstract

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 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 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 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)4thereby 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.

Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

“…Indeed, there are several recent reports which demonstrate that, contrary to lay press reports of antioxidants being beneficial dietary supplements(7), these compounds can in fact accelerate lung cancer progression in mice(13) and promote distant metastases in human melanoma cells(50,51); similar findings have most recently been shown in pancreatic cancer by deletion of malic enzyme 2(52). While ccRCC cells have been shown to require glutamine for growth and survival(19), the direct role of this amino acid in the response of ccRCC cells and kidney cancers to oxidative stress has, prior to the current study, not been described.…”

Large‐scale profiling of serum metabolites in African American and European American patients with bladder cancer reveals metabolic pathways associated with patient survival

“…There was no clinical association of pathway genes in EA BLCA with survival in AA BLCA. 10 The metabolic role of ME3 in the progression of AA BLCA needs further investigation. This is the first study to report disparities related to metabolism-related genes associated with poor survival among AAs with BLCA.…”

“…51 Recent studies in pancreatic cancer have revealed that ME3 depletion selectively kills ME2-null cancer cells, and this confers its role in cancer. 10 The metabolic role of ME3 in the progression of AA BLCA needs further investigation.…”

“…9 In contrast, ME3 oxidatively decarboxylates malate to pyruvate and is essential for NADP/ NADPH homeostasis. 10 Because of the importance of the amino acid metabolism pathway of cancer cell proliferation, drugs targeting amino acid metabolism may reduce BLCA growth.…”

Targeting Metabolism for Cancer Therapy

“…Pancreatic ductal adenocarcinoma (PDAC) cells exhibiting homozygous deletion of the tumor suppressor SMAD4 often lose malic enzyme 2 (ME2) expression due to the chromosomal proximity of the two genes. Targeting the malic enzyme 3 (ME3) isoform was found to impair tumor proliferation of PDAC xenografts lacking ME2 expression, but had no effect on tumors with intact ME2 (Dey et al, 2017). Similarly, the gene encoding enolase 1 (ENO1) is on the tumor-suppressor locus 1p36, and undergoes homozygous deletion in 1–5% of GBM cancers.…”