Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer
Open accessAbstract
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.
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PDAC cells with homozygous deletion of SMAD4 often lose ME2 due to chromosomal proximity; targeting ME3 impairs tumor proliferation of PDAC xenografts lacking ME2 but has no effect on tumors with intact ME2.
“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).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Dey et al., 2017
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Self-citation
- Authors
- Dey, P., Baddour, J., Muller, F., Wu, C. C., Wang, H., Liao, W.-T., 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, Y. A., Nagrath, D., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Rice University (US)
- Corresponding author
- Wang, Y. Alan
- Nagrath, Deepak
- DePinho, Ronald A.
- ORCID
- Venue
- Nature
- Published
- 2017-01-18
- Volume
- 542
- Issue
- 7639
- Pages
- 119-123
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5398413
- OpenAlex
- W2576681512
- Cited by
- 264
- References
- 37
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 23 · 2023: 24 · 2022: 27 · 2021: 34 · 2020: 36 · 2019: 33 · 2018: 23 · 2017: 21
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-09-17)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R00CA218891, K99CA218891, P30CA016672, P01CA117969)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pancreatic ductal adenocarcinoma, NADPH regeneration, reactive oxygen species, AMPK, SREBP1, BCAT2, glutamate metabolism, de novo nucleotide synthesis, mitochondrial metabolism, therapeutic target
- MeSH terms
- Amino Acids, Branched-Chain, Transaminases, Animals, Humans, Ketoglutaric Acids, Malate Dehydrogenase, Male, Mitochondria, NADP, Pancreatic Neoplasms, Pregnancy Proteins, Minor Histocompatibility Antigens, Gene Deletion, Reactive Oxygen Species, Carcinoma, Pancreatic Ductal, Mice, Sterol Regulatory Element Binding Protein 1, Biocatalysis, AMP-Activated Protein Kinases
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