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Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells

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العنوان: Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells
المؤلفون: Jennifer E. Hrabe, Brianne R. O’Leary, Melissa A. Fath, Samuel N. Rodman, Anna M. Button, Frederick E. Domann, Douglas R. Spitz, James J. Mezhir
المصدر: Redox Biology, Vol 5, Iss , Pp 319-327 (2015)
بيانات النشر: Elsevier, 2015.
سنة النشر: 2015
المجموعة: LCC:Medicine (General)
LCC:Biology (General)
مصطلحات موضوعية: Medicine (General), R5-920, Biology (General), QH301-705.5
الوصف: Transforming growth factor β-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5 µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10 mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH) and glutathione disulfide (GSSG). Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1-induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors. Keywords: TAK1, KRAS, Colorectal cancer, Thioredoxin, Treatment resistance
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2213-2317
Relation: http://www.sciencedirect.com/science/article/pii/S2213231715000555; https://doaj.org/toc/2213-2317
DOI: 10.1016/j.redox.2015.06.004
URL الوصول: https://doaj.org/article/3e95cf96eb884863b53eab207ac06200
رقم الأكسشن: edsdoj.3e95cf96eb884863b53eab207ac06200
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:22132317
DOI:10.1016/j.redox.2015.06.004