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 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.
authors.affiliation: 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.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Harris
authors.affiliation: 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.
authors.forename: Aislinn E
authors.initials: AE
authors.lastname: Treloar
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gorrini
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Kim Chung
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Ka Yi
authors.initials: KY
authors.lastname: Yung
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Department of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Knobbe-Thomsen
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Cox
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Elia
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: David W
authors.initials: DW
authors.lastname: Cescon
authors.affiliation: 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.
authors.forename: Adewunmi
authors.initials: A
authors.lastname: Adeoye
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.affiliation: 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.
authors.forename: Sam D
authors.initials: SD
authors.lastname: Molyneux
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: Division of Cell Function Research Support, Biomedical Research Support Center, Nagasaki University School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, 620 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: 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.
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.affiliation: 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.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.affiliation: 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.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Done
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Ching-Wan
authors.initials: CW
authors.lastname: Lam
authors.affiliation: 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.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000235:genetics; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D013879:Thioredoxins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione