Abstract
We have developed a novel therapeutic paradigm (“metabolic priming”) for cancer whereby restriction of the essential amino acid methionine activates a number of cell-stress-response pathways that can be selectively targeted to enhance the therapeutic impact of methionine restriction. One example of metabolic priming is the combination of methionine restriction with proapoptotic TRAIL receptor-2 (TRAIL-R2) agonists. Methionine restriction enhances the cell surface expression of TRAIL-R2 selectively in transformed breast epithelial cells and renders them more susceptible to cell death induction by TRAIL-R2 agonists in cellular and murine models of breast cancer. This methods review focuses on preclinical models of breast cancer to investigate metabolic priming by methionine restriction. Multiple cell-based methods are detailed to measure cell viability, cell survival, caspase activity, apoptosis, and matrix detachment-induced cell death (anoikis). In addition, we describe an orthotopic model of metastatic breast cancer that utilizes mCherry-fluorescently-labeled human breast cancer cells. This model captures the entire metastatic cascade from the mammary gland to the lung and mimics key features of the human disease. These breast-cancer models can be readily adapted to other tumor types. Overall, we provide a stepwise, translationally-relevant approach to study metabolic priming in the context of cancer.
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Acknowledgments
We are indebted to Robin Humphreys for providing agonistic TRAIL receptor mAbs. This work was supported by grants from the V Foundation for Cancer Research, Breast Cancer Research Foundation, Avon Breast Cancer Crusade, UW Carbone Cancer Center pilot funding, and the Wisconsin Partnership Program.
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Strekalova, E., Malin, D., Rajanala, H., Cryns, V.L. (2019). Preclinical Breast Cancer Models to Investigate Metabolic Priming by Methionine Restriction. In: Hoffman, R. (eds) Methionine Dependence of Cancer and Aging. Methods in Molecular Biology, vol 1866. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8796-2_6
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DOI: https://doi.org/10.1007/978-1-4939-8796-2_6
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