Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation
Open accessAbstract
Rho GTPases impact a number of activities important for oncogenesis. We describe a small molecule inhibitor that blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NF-κB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.
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Inhibitors of glutaminase efficiently induce cancer cell death through dysregulation of the antioxidant system.
“In addition, inhibitors of the enzyme glutaminase (GLS) that converts glutamine to glutamate, which is subsequently transformed to GSH via the glutamate–cysteine ligase complex, efficiently induce cancer cell death through dysregulation of their antioxidant system72.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [72]
The Results section (“968 blocks the transforming activity of human breast cancer cells”; page unavailable) reports that the glutaminase inhibitor 968 inhibited cancer-cell growth and colony formation. It does not establish that the inhibitor induced cell death or that its effects resulted from dysregulation of the antioxidant system; the Discussion instead emphasizes effects on glutaminase activity and oncogenic transformation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGLS inhibition suppresses proliferation.
“GLS inhibition suppresses proliferation, and GLS inhibitors are being evaluated in clinical studies for a number of cancers.31,38,39”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [38]
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- Authors
- Wang, J.-B., Erickson, J. W., Fuji, R., Ramachandran, S., Gao, P., Dinavahi, R., Wilson, K. F., Ambrosio, A. L. B., Dias, S. M. G., Dang, C. V., & Cerione, R. A.
- Affiliations
- Cornell University (US)
- Johns Hopkins University (US)
- Corresponding author
- Cerione, Richard A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 18
- Issue
- 3
- Pages
- 207-219
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3078749
- OpenAlex
- W2056174640
- Cited by
- 821
- References
- 38
- Citations by year
- 2026: 18 · 2025: 36 · 2024: 35 · 2023: 48 · 2022: 55 · 2021: 65 · 2020: 55 · 2019: 53 · 2018: 60 · 2017: 66 · 2016: 72 · 2015: 55 · 2014: 60 · 2013: 66 · 2012: 45
- FWCI
- 14.31
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-10-19)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM047458, R01GM040654, R01GM061762)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Rho GTPases, oncogenic transformation, small molecule inhibitors, glutamine metabolism, NF-κB, breast cancer, B lymphoma, fibroblasts, cellular metabolism, cancer cell growth
- MeSH terms
- Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Enzyme Inhibitors, Female, Fibroblasts, Glutaminase, Humans, Mitochondria, Transfection, Signal Transduction, rho GTP-Binding Proteins, NIH 3T3 Cells, Cell Line, Tumor, Mice
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