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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Metabolite Profiling Reveals the Glutathione Biosynthetic Pathway as a Therapeutic Target in Triple-Negative Breast Cancer
Molecular cancer therapeutics, v 17(1), pp 264-275
01 Jan 2018
PMID: 29021292
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple-negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry-based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from nontransformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal-like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal-like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacologic inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of g-glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by g-glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond. (C) 2017 AACR.
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Details
- Title
- Metabolite Profiling Reveals the Glutathione Biosynthetic Pathway as a Therapeutic Target in Triple-Negative Breast Cancer
- Creators
- Alexander Beatty - Fox Chase Cancer CenterLauren S. Fink - Fox Chase Cancer CenterTanu Singh - Fox Chase Cancer CenterAlexander Strigun - Metanomics GmbH & Metanomics Health GmbH, Berlin, Germany.Erik Peter - Metanomics GmbH & Metanomics Health GmbH, Berlin, Germany.Christina M. Ferrer - Drexel UniversityEmmanuelle Nicolas - Fox Chase Cancer CenterKathy Q. Cai - Fox Chase Cancer CenterTimothy P. Moran - Fox Chase Cancer CenterMauricio J. Reginato - Drexel UniversityUlrike Rennefahrt - Metanomics GmbH & Metanomics Health GmbH, Berlin, Germany.Jeffrey R. Peterson - Fox Chase Cancer Center
- Publication Details
- Molecular cancer therapeutics, v 17(1), pp 264-275
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 12
- Grant note
- P30CA006927 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01GM083025 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30 CA006927 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01 GM083025 / NIGMS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000419148400025
- Scopus ID
- 2-s2.0-85040037912
- Other Identifier
- 991019169591204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology