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Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia
Open accessPublished version of a preprint
Abstract
The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival. Significance: In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth. Cancer Discov; 4(12); 1406–17. ©2014 AACR. See related commentary by Martínez-Reyes and Chandel, p. 1371 This article is highlighted in the In This Issue feature, p. 1355
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“SHMT2 is unlikely to directly demethylate trigonelline because it is not a N-methyltransferase and is known to cross-talk with NAD+ metabolism indirectly37,38.”
From Trigonelline Is an NAD+ Precursor That Improves Muscle Function during Ageing and Is Reduced in Human Sarcopenia (2024) · cites this paper as [37]
In the citing paper
“Loss of SHMT2 in hypoxic cells increases reactive oxygen species (ROS) levels, resulting in cell death.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [61]
In the citing paper
“SHMT2 also plays a role in redox balance.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [126]
In the citing paper
“Hypoxia induces SHMT2 expression and was found to be necessary for redox homeostasis and cell survival under hypoxic conditions.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [126]
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“Indeed, most cytosolic NADPH (> 80%) is devoted to biosynthesis rather than to redox defense (Ye et al., 2014).”
BackgroundDeacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
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“The mitochondrial isoform of SHMT (SHMT2) likely plays a critical role in this block, as it generates folates from serine for nucleotide biosynthesis in cell lines [33,34], and coordination of this enzyme with activity of the glycine cleavage system can impact proliferation of poorly vascularized tumors [35].”
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“Targeting SHMT2 reduced survival of the hypoxic transformed cells, which were rescued by the antioxidant N-acetylcysteine (73).”
BackgroundRedox Potential of Antioxidants in Cancer Progression and Prevention
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“(2014) demonstrated a decrease in the NAD PH/ NADP ratio with SHMT2 knockdown only in hypoxic conditions in neuroblastoma cells (Fan et al., 2014; Ye et al., 2014).”
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BackgroundMitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy
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Self-citationSHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
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Self-citationReprogramming of serine, glycine and one-carbon metabolism in cancer
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Self-citationSerine catabolism generates liver NADPH and supports hepatic lipogenesis
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Self-citationRedox Regulation in Cancer Cells during Metastasis
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“Inhibition of either phosphoglycerate dehydrogenase, an enzyme involved in serine synthesis, or serine hydroxymethyltransferase, an enzyme involved in serine degradation, increases ROS levels and reduces the formation of metastatic tumors (88, 89).”
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Metadata
- Authors
- Ye, J., Fan, J., Venneti, S., Wan, Y.-W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., Qing, G., Liu, Z., Simon, M. C., Rabinowitz, J. D., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Princeton University (US)
- Baylor College of Medicine (US)
- Children's Hospital of Philadelphia (US)
- 1Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
- Huazhong University of Science and Technology (CN)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-12-01
- Volume
- 4
- Issue
- 12
- Pages
- 1406-1417
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4258153
- OpenAlex
- W2163404652
- Cited by
- 452
- References
- 50
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 40 · 2023: 38 · 2022: 46 · 2021: 58 · 2020: 67 · 2019: 36 · 2018: 21 · 2017: 27 · 2016: 34 · 2015: 19 · 2014: 5
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (K08CA181475, P01CA104838, K99CA184239, R01CA105463, P30CA008748, R01CA163591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- serine catabolism, SHMT2, hypoxia, mitochondrial redox balance, NADPH/NADP+ ratio, reactive oxygen species, c-Myc, tumor growth, neuroblastoma, hypoxia-inducible factor-1α, hypoxia-induced cell death, cancer metabolism
- MeSH terms
- Animals, Hypoxia, Base Sequence, Cell Survival, Disease Models, Animal, Gene Amplification, Homeostasis, Humans, Mitochondria, Models, Biological, Molecular Sequence Data, Neoplasms, Oxidation-Reduction, Promoter Regions, Genetic, Serine, Glycine Hydroxymethyltransferase, Gene Expression, Genes, myc, Reactive Oxygen Species, Cell Line, Tumor, Tumor Burden, Phosphoglycerate Dehydrogenase, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Gene Knockdown Techniques, Heterografts
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