Cited by 328Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismCancer and biochemical research

Comparative Metabolic Flux Profiling of Melanoma Cell Lines

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Scott, David A., Richardson, Adam D., Filipp, Fabian V., Knutzen, Christine A., Chiang, Gary G., Ronai, Ze'ev A., Osterman, Andrei L., Smith, Jeffrey W.·2011·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m111.282046

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  • Malignant cells use glutaminolysis under hypoxic conditions.

    “Numerous studies have reported that malignant cells use glutaminolysis under hypoxic conditions [82,83].”
  • Tumor cells with mutations in the TCA cycle or ETC, or with hypoxia-induced suppression of oxidative metabolism, use reductive carboxylation of α-KG to produce citrate and other precursors during growth.

    “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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  1. Cheng, T., Sudderth, J., Yang, C., Mullen, A. R., Jin, E. S., Matés, J. M., and DeBerardinis, R. J. (2011) Proc. Natl. Acad. Sci. U.S.A. 108, 8674 -8679
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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.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2011-12
Volume
286
Issue
49
Pages
42626-42634
ISSN
0021-9258 (ISSN-L)
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
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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