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Cancer Cell. 2015 Feb 9;27(2):211-22. doi: 10.1016/j.ccell.2014.11.019. Epub 2015 Jan 22.

Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

Author information

1
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
2
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
3
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Infection and Host Defense, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
4
Department of Pathology, The University of Hong Kong, Hong Kong, China.
5
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Infection and Immunity, Luxembourg Institute of Health, 84, Val Fleuri, 1526 Luxembourg, Luxembourg.
6
Department of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany.
7
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Laboratory Medicine Program, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
8
Department of Medical Biophysics, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Ontario Cancer Institute, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
9
Division of Cell Function Research Support, Biomedical Research Support Center, Nagasaki University School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
10
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
11
The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address: tmak@uhnres.utoronto.ca.

Erratum in

  • Cancer Cell. 2015 Feb 9;27(2):314.

Abstract

Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

PMID:
25620030
DOI:
10.1016/j.ccell.2014.11.019
[Indexed for MEDLINE]
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