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

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

doi:10.1016/j.redox.2015.06.004

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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

Journal article

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Peer reviewed

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

Jennifer E Hrabe, Brianne R O'Leary, Melissa A Fath, Samuel N Rodman, Anna M Button, Frederick E Domann, Douglas R Spitz and James J Mezhir

Redox biology, Vol.5, pp.319-327

08/2015

DOI: 10.1016/j.redox.2015.06.004

PMCID: PMC4491644

PMID: 26114584

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Abstract

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 5µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM 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.

ras Proteins - genetics

Zearalenone - therapeutic use

Glutathione - metabolism

Colonic Neoplasms - drug therapy

Humans

ras Proteins - metabolism

Transplantation, Heterologous

Antineoplastic Agents - therapeutic use

Colonic Neoplasms - metabolism

Antineoplastic Agents - toxicity

Auranofin - toxicity

Thioredoxin-Disulfide Reductase - metabolism

Female

Thioredoxins - metabolism

Auranofin - therapeutic use

MAP Kinase Kinase Kinases - antagonists & inhibitors

Cell Survival - drug effects

Auranofin - chemistry

HCT116 Cells

Zearalenone - chemistry

Zearalenone - analogs & derivatives

MAP Kinase Kinase Kinases - metabolism

Antineoplastic Agents - chemistry

Zearalenone - toxicity

Animals

Mice, Nude

Colonic Neoplasms - pathology

Cell Line, Tumor

Mice

Thioredoxin-Disulfide Reductase - antagonists & inhibitors

Mutation

Oxidative Stress - drug effects

Details

Title: Subtitle: Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells
Creators: Jennifer E Hrabe - Department of Surgery, Division of Surgical Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Brianne R O'Leary - Department of Surgery, Division of Surgical Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Melissa A Fath - Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Samuel N Rodman - Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Anna M Button - Department of Biostatistics, University of Iowa, Iowa City, IA, USA
Frederick E Domann - Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Douglas R Spitz - Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
James J Mezhir - Department of Surgery, Division of Surgical Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Department of Radiation Oncology, Free Radical and Radiation Biology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA. Electronic address: james-mezhir@uiowa.edu
Resource Type: Journal article
Publication Details: Redox biology, Vol.5, pp.319-327
DOI: 10.1016/j.redox.2015.06.004
PMID: 26114584
PMCID: PMC4491644
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Netherlands
Grant note: R21CA161182 / NCI NIH HHS P30 ES005605 / NIEHS NIH HHS T32 CA148062 / NCI NIH HHS R01CA182804 / NCI NIH HHS R01CA115438 / NCI NIH HHS T32CA148062 / NCI NIH HHS R01 CA182804 / NCI NIH HHS NIHP30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 08/2015
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984047988602771

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