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Supplementary Figure from Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102

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posted on 2023-03-31, 23:42 authored by Caitlyn B. Brashears, Bethany C. Prudner, Richa Rathore, Katharine E. Caldwell, Carina A. Dehner, Jane L. Buchanan, Sara E.S. Lange, Neal Poulin, Jennifer K. Sehn, Jason Roszik, Dirk Spitzer, Kevin B. Jones, Regis O'Keefe, Torsten O. Nielsen, Eric B. Taylor, Jason M. Held, William Hawkins, Brian A. Van Tine
Supplementary Figure from Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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CJ's Journey

Wipe Out Kids Cancer

The Sarcoma Foundation of America

Sarcoma Alliance for Research and Collaboration

Canadian Cancer Society (Société canadienne du cancer)

the Sarcoma Cancer Foundation of Canada Beth England's Sarcoma Research Fund

Pedal for Home Impact Grant of the Canadian Cancer Society

Washington University in St. Louis School of Medicine MSTP training grant

Washington University Surgical Oncology Training Gran

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

United States Department of Health and Human Services

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University of Iowa Medical Scientist Training Program

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ARTICLE ABSTRACT

To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients.See related commentary by Subbiah and Gan, p. 3408

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    Clinical Cancer Research

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    cancer

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