[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Harris, Isaac S; 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
Treloar, Aislinn E; 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
Inoue, Satoshi; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Sasaki, Masato; 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
Gorrini, Chiara; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Lee, Kim Chung; Department of Pathology, The University of Hong Kong, Hong Kong, China
Yung, Ka Yi; Department of Pathology, The University of Hong Kong, Hong Kong, China
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
Knobbe-Thomsen, Christiane B; Department of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany
Cox, Maureen A; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Elia, Andrew; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Berger, Thorsten; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Cescon, David W; 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
Adeoye, Adewunmi; 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
Brüstle, Anne; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Molyneux, Sam D; 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
Mason, Jacqueline M; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Li, Wanda Y; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Yamamoto, Kazuo; Division of Cell Function Research Support, Biomedical Research Support Center, Nagasaki University School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
Wakeham, Andrew; The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada
Berman, Hal K; 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
Khokha, Rama; 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
Done, Susan J; 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
Kavanagh, Terrance J; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
Lam, Ching-Wan; Department of Pathology, The University of Hong Kong, Hong Kong, China
Mak, Tak W; 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
We are very grateful for the generous gift of the Nrf2 antibody from Dr. Edward Schmidt (Montana State University). We would like to thank Mary Saunders, Jonathan L. Coloff, and Lisa L. Gallegos for scientific editing, Irene Ng for administrative help, and Marsha J. Barrett for discussions. This work was supported by a PGS-D grant from the Natural Sciences and Engineering Council of Canada (I.S.H.), a fellowship grant from the German Research Foundation (D.B.), funding by the ATTRACT program of the Luxembourg National Research Fund (D.B.), and a fellowship (I.S.H.) and grants (T.W.M.) from the Canadian Institutes of Health Research.
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