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Targeting Glutamine Metabolism in Breast Cancer with Aminooxyacetate
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Abstract
Purpose: Glutamine addiction in c-MYC–overexpressing breast cancer is targeted by the aminotransferase inhibitor, aminooxyacetate (AOA). However, the mechanism of ensuing cell death remains unresolved. Experimental Design: A correlation between glutamine dependence for growth and c-MYC expression was studied in breast cancer cell lines. The cytotoxic effects of AOA, its correlation with high c-MYC expression, and effects on enzymes in the glutaminolytic pathway were investigated. AOA-induced cell death was assessed by measuring changes in metabolite levels by magnetic resonance spectroscopy (MRS), the effects of amino acid depletion on nucleotide synthesis by cell-cycle and bromodeoxyuridine (BrdUrd) uptake analysis, and activation of the endoplasmic reticulum (ER) stress–mediated pathway. Antitumor effects of AOA with or without common chemotherapies were determined in breast cancer xenografts in immunodeficient mice and in a transgenic MMTV-rTtA-TetO-myc mouse mammary tumor model. Results: We established a direct correlation between c-MYC overexpression, suppression of glutaminolysis, and AOA sensitivity in most breast cancer cells. MRS, cell-cycle analysis, and BrdUrd uptake measurements indicated depletion of aspartic acid and alanine leading to cell-cycle arrest at S-phase by AOA. Activation of components of the ER stress–mediated pathway, initiated through GRP78, led to apoptotic cell death. AOA inhibited growth of SUM159, SUM149, and MCF-7 xenografts and c-myc–overexpressing transgenic mouse mammary tumors. In MDA-MB-231, AOA was effective only in combination with chemotherapy. Conclusions: AOA mediates its cytotoxic effects largely through the stress response pathway. The preclinical data of AOA's effectiveness provide a strong rationale for further clinical development, particularly for c-MYC–overexpressing breast cancers. Clin Cancer Res; 21(14); 3263–73. ©2015 AACR.
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“Glutamate consumption by aminotransferases to generate NEAAs has also been indicated to be required for tumor growth in diverse cancer types29,40–42.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [41]
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Metadata
- Authors
- Korangath, P., Teo, W. W., Sadik, H., Han, L., Mori, N., Huijts, C. M., Wildes, F., Bharti, S., Zhang, Z., Santa-Maria, C. A., Tsai, H., Dang, C. V., Stearns, V., Bhujwalla, Z. M., & Sukumar, S.
- Affiliations
- Johns Hopkins University (US)
- 2Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- 1Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
- University of Pennsylvania (US)
- Corresponding author
- Sukumar, Saraswati
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-07-14
- Volume
- 21
- Issue
- 14
- Pages
- 3263-3273
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4696069
- OpenAlex
- W2011628468
- Cited by
- 182
- References
- 40
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 18 · 2023: 7 · 2022: 30 · 2021: 15 · 2020: 28 · 2019: 13 · 2018: 13 · 2017: 17 · 2016: 15 · 2015: 3
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Cancer Institute (R01CA051497, P30CA060553, P30CA006973, P30CA016520)
- 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 › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- aminooxyacetic acid, glutamine metabolism, glutaminolysis, MYC overexpression, breast cancer, endoplasmic reticulum stress, GRP78, apoptosis, S phase arrest, amino acid starvation, nucleotide synthesis, combination chemotherapy, xenografts
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Aminooxyacetic Acid, Animals, Antineoplastic Agents, Breast Neoplasms, Enzyme Inhibitors, Female, Glutamine, Humans, Mice, Transgenic, Magnetic Resonance Spectroscopy, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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