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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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In the citing paper
“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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Citations
Cites
The metabolism of tumors in the body
Warburg, O., Wind, F., & Negelein, E. (1927) · Journal of General Physiology · doi:10.1085/jgp.8.6.519 · Cited by 4,416 · cited 1×
“Warburg discovered in the 1920s that tumor cells show high glucose consumption (1), oncologists have been interested in finding out how tumor cells adapt metabolic pathways to obtain advantages in cell proliferation and tumor growth.”
BackgroundKim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · cited 2×
“The upregulation of these enzymes not only accelerates glucose uptake and glycolysis but also promotes the Warburg effect in two ways: On the one hand, LDHA channels pyruvate toward lactate production; on the other hand, pyruvate entry into the TCA cycle is blocked by PDK1, which phosphorylates and inhibits pyruvate d…”
BackgroundHIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L., & Denko, N. C. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.01.012 · Cited by 2,267 · cited 1×
“The upregulation of these enzymes not only accelerates glucose uptake and glycolysis but also promotes the Warburg effect in two ways: On the one hand, LDHA channels pyruvate toward lactate production; on the other hand, pyruvate entry into the TCA cycle is blocked by PDK1, which phosphorylates and inhibits pyruvate d…”
BackgroundRhodes, D. R., Sundaram, S. K., Mahavisno, V., Varambally, R., Yu, J., Briggs, B., Barrette, T. R., Anstett, M. J., Kincead-Beal, C., Kulkarni, P., et al. (2007) · Neoplasia · doi:10.1593/neo.07112 · Cited by 2,057
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Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.
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“Because PGK1 and LDHA are both HIF1α targets that are induced upon hypoxia (16, 17), we asked whether SHMT2 is also regulated under hypoxia through HIF.”
BackgroundHöckel, M., Schlenger, K., Aral, B., Mitze, M., Schäffer, U., & Vaupel, P. W. (1996) · PubMed · Cited by 1,727
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683
Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing
Guzy, R. D., Hoyos, B., Robin, E., Chen, H., Liu, L., Mansfield, K. D., Simon, M. C., Hammerling, U., & Schumacker, P. T. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.001 · Cited by 1,545
Self-citationTranscriptional Amplification in Tumor Cells with Elevated c-Myc
Lin, C. Y., Lovén, J., Rahl, P. B., Paranal, R. M., Burge, C. B., Bradner, J. E., Lee, T. I., & Young, R. A. (2012) · Cell · doi:10.1016/j.cell.2012.08.026 · Cited by 1,543
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The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926
Self-citationFundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654
One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239
“In MYC amplified cancer cell lines grown under hypoxia, SHMT2 is induced and shRNA knockdown leads to decreases in NADPH and impaired survival (Ye et al., 2014).”
BackgroundSelf-citationFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
“BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
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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