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Comparative Metabolic Flux Profiling of Melanoma Cell Lines
Open accessAbstract
Metabolic rewiring is an established hallmark of cancer, but the details of this rewiring at a systems level are not well characterized. Here we acquire this insight in a melanoma cell line panel by tracking metabolic flux using isotopically labeled nutrients. Metabolic profiling and flux balance analysis were used to compare normal melanocytes to melanoma cell lines in both normoxic and hypoxic conditions. All melanoma cells exhibited the Warburg phenomenon; they used more glucose and produced more lactate than melanocytes. Other changes were observed in melanoma cells that are not described by the Warburg phenomenon. Hypoxic conditions increased fermentation of glucose to lactate in both melanocytes and melanoma cells (the Pasteur effect). However, metabolism was not strictly glycolytic, as the tricarboxylic acid (TCA) cycle was functional in all melanoma lines, even under hypoxia. Furthermore, glutamine was also a key nutrient providing a substantial anaplerotic contribution to the TCA cycle. In the WM35 melanoma line glutamine was metabolized in the "reverse" (reductive) direction in the TCA cycle, particularly under hypoxia. This reverse flux allowed the melanoma cells to synthesize fatty acids from glutamine while glucose was primarily converted to lactate. Altogether, this study, which is the first comprehensive comparative analysis of metabolism in melanoma cells, provides a foundation for targeting metabolism for therapeutic benefit in melanoma.
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“Numerous studies have reported that malignant cells use glutaminolysis under hypoxic conditions [82,83].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [82]
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“tumor cells with mutations in the TCA cycle or ETC (Mullen et al., 2011), or with hypoxia-induced suppression of oxidative metabolism (Metallo et al., 2011; Scott et al., 2011; Wise et al., 2011) use reductive carboxylation of α-KG to produce citrate and other precursors during growth.”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Scott et al., 2011
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Metadata
- Authors
- Scott, D. A., Richardson, A. D., Filipp, F. V., Knutzen, C. A., Chiang, G. G., Ronai, Z. A., Osterman, A. L., & Smith, J. W.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Osterman, Andrei L.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 286
- Issue
- 49
- Pages
- 42626-42634
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3234981
- OpenAlex
- W1976603231
- Cited by
- 328
- References
- 44
- Citations by year
- 2026: 7 · 2025: 21 · 2024: 16 · 2023: 15 · 2022: 21 · 2021: 32 · 2020: 30 · 2019: 21 · 2018: 22 · 2017: 25 · 2016: 20 · 2015: 33 · 2014: 20 · 2013: 20 · 2012: 25
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-147978, R00CA154887, CA-154887, K99CA154887, R21CA147978, P01CA128814, CA-128814)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- melanoma, Warburg effect, hypoxia, Pasteur effect, glycolysis, lactic acid production, TCA cycle, glutamine metabolism, reductive TCA cycle, fatty acid synthesis, melanocytes, isotopic labeling, flux balance analysis, metabolic therapy
- MeSH terms
- Hypoxia, Citric Acid Cycle, Fermentation, Glucose, Glutamine, Glycolysis, Humans, Ketoglutaric Acids, Gas Chromatography-Mass Spectrometry, Melanocytes, Melanoma, Models, Biological, Skin Neoplasms, Lactic Acid, Cell Line, Tumor
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