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

Research output: Contribution to journalArticlepeer-review

702 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 languageEnglish
Pages (from-to)211-222
Number of pages12
JournalCancer Cell
Volume27
Issue number2
DOIs
Publication statusPublished - 2015 Feb 9
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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