Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

Isaac S. Harris; Aislinn E. Treloar; Satoshi Inoue; Masato Sasaki; Chiara Gorrini; Kim Chung Lee; Ka Yi Yung; Dirk Brenner; Christiane B. Knobbe-Thomsen; Maureen A. Cox; Andrew Elia; Thorsten Berger; David W. Cescon; Adewunmi Adeoye; Anne Brüstle; Sam D. Molyneux; Jacqueline M. Mason; Wanda Y. Li; Kazuo Yamamoto; Andrew Wakeham; Hal K. Berman; Rama Khokha; Susan J. Done; Terrance J. Kavanagh; Ching Wan Lam; Tak W. Mak

doi:10.1016/j.ccell.2014.11.019

Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

Isaac S. Harris, Aislinn E. Treloar, Satoshi Inoue, Masato Sasaki, Chiara Gorrini, Kim Chung Lee, Ka Yi Yung, Dirk Brenner, Christiane B. Knobbe-Thomsen, Maureen A. Cox, Andrew Elia, Thorsten Berger, David W. Cescon, Adewunmi Adeoye, Anne Brüstle, Sam D. Molyneux, Jacqueline M. Mason, Wanda Y. Li, Kazuo Yamamoto, Andrew WakehamHal K. Berman, Rama Khokha, Susan J. Done, Terrance J. Kavanagh, Ching Wan Lam, Tak W. Mak^*

^*Corresponding author for this work

Experimental and Molecular Immunology

Research output: Contribution to journal › Article › Research › peer-review

613 Citations (Scopus)

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 canbe 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 invitro and invivo, demonstrating theimportance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

Original language	English
Pages (from-to)	211-222
Number of pages	12
Journal	Cancer Cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2014.11.019
Publication status	Published - 9 Feb 2015

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Harris, I. S., Treloar, A. E., Inoue, S., Sasaki, M., Gorrini, C., Lee, K. C., Yung, K. Y., Brenner, D., Knobbe-Thomsen, C. B., Cox, M. A., Elia, A., Berger, T., Cescon, D. W., Adeoye, A., Brüstle, A., Molyneux, S. D., Mason, J. M., Li, W. Y., Yamamoto, K., ... Mak, T. W. (2015). Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression. Cancer Cell, 27(2), 211-222. https://doi.org/10.1016/j.ccell.2014.11.019

@article{2d25d48f1ead49eab7b72965d6cab54b,

title = "Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression",

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 canbe 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 invitro and invivo, demonstrating theimportance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.",

author = "Harris, {Isaac S.} and Treloar, {Aislinn E.} and Satoshi Inoue and Masato Sasaki and Chiara Gorrini and Lee, {Kim Chung} and Yung, {Ka Yi} and Dirk Brenner and Knobbe-Thomsen, {Christiane B.} and Cox, {Maureen A.} and Andrew Elia and Thorsten Berger and Cescon, {David W.} and Adewunmi Adeoye and Anne Br{\"u}stle and Molyneux, {Sam D.} and Mason, {Jacqueline M.} and Li, {Wanda Y.} and Kazuo Yamamoto and Andrew Wakeham and Berman, {Hal K.} and Rama Khokha and Done, {Susan J.} and Kavanagh, {Terrance J.} and Lam, {Ching Wan} and Mak, {Tak W.}",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = feb,

day = "9",

doi = "10.1016/j.ccell.2014.11.019",

language = "English",

volume = "27",

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journal = "Cancer Cell",

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Harris, IS, Treloar, AE, Inoue, S, Sasaki, M, Gorrini, C, Lee, KC, Yung, KY, Brenner, D, Knobbe-Thomsen, CB, Cox, MA, Elia, A, Berger, T, Cescon, DW, Adeoye, A, Brüstle, A, Molyneux, SD, Mason, JM, Li, WY, Yamamoto, K, Wakeham, A, Berman, HK, Khokha, R, Done, SJ, Kavanagh, TJ, Lam, CW & Mak, TW 2015, 'Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression', Cancer Cell, vol. 27, no. 2, pp. 211-222. https://doi.org/10.1016/j.ccell.2014.11.019

TY - JOUR

T1 - Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

AU - Harris, Isaac S.

AU - Treloar, Aislinn E.

AU - Inoue, Satoshi

AU - Sasaki, Masato

AU - Gorrini, Chiara

AU - Lee, Kim Chung

AU - Yung, Ka Yi

AU - Brenner, Dirk

AU - Knobbe-Thomsen, Christiane B.

AU - Cox, Maureen A.

AU - Elia, Andrew

AU - Berger, Thorsten

AU - Cescon, David W.

AU - Adeoye, Adewunmi

AU - Brüstle, Anne

AU - Molyneux, Sam D.

AU - Mason, Jacqueline M.

AU - Li, Wanda Y.

AU - Yamamoto, Kazuo

AU - Wakeham, Andrew

AU - Berman, Hal K.

AU - Khokha, Rama

AU - Done, Susan J.

AU - Kavanagh, Terrance J.

AU - Lam, Ching Wan

AU - Mak, Tak W.

N1 - Funding Information: 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. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/2/9

Y1 - 2015/2/9

N2 - 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 canbe 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 invitro and invivo, demonstrating theimportance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

AB - 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 canbe 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 invitro and invivo, demonstrating theimportance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

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U2 - 10.1016/j.ccell.2014.11.019

DO - 10.1016/j.ccell.2014.11.019

M3 - Article

C2 - 25620030

AN - SCOPUS:84922783167

SN - 1535-6108

VL - 27

SP - 211

EP - 222

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

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