Journal article
Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102
Clinical cancer research, Vol.28(16), pp.OF1-OF17
04/29/2022
DOI: 10.1158/1078-0432.CCR-22-0470
PMCID: PMC9378556
PMID: 35421237
Abstract
Abstract
Purpose:
To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis.
Experimental Design:
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.
Results:
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.
Conclusions:
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.
Details
- Title: Subtitle
- Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102
- Creators
- Caitlyn B. Brashears - Washington University in St. LouisBethany C. Prudner - Washington University in St. LouisRicha Rathore - Washington University in St. LouisKatharine E. Caldwell - Washington University in St. LouisCarina A. Dehner - Washington University in St. LouisJane L. Buchanan - University of IowaSara E.S. Lange - Washington University in St. LouisNeal Poulin - University of British ColumbiaJennifer K. Sehn - Saint Louis UniversityJason Roszik - The University of Texas MD Anderson Cancer CenterDirk Spitzer - Washington University in St. LouisKevin B. Jones - Huntsman Cancer InstituteRegis O'Keefe - University of RochesterTorsten O. Nielsen - University of British ColumbiaEric B. Taylor - University of IowaJason M. Held - Washington University in St. LouisWilliam Hawkins - Washington University in St. LouisBrian A. Van Tine - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.28(16), pp.OF1-OF17
- DOI
- 10.1158/1078-0432.CCR-22-0470
- PMID
- 35421237
- PMCID
- PMC9378556
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- name: National Cancer Institute, award: RO1 CA227115; name: CJ's Journey; DOI: 10.13039/100003517, name: Wipe Out Kids Cancer; DOI: 10.13039/100003341, name: The Sarcoma Foundation of America; name: Sarcoma Alliance for Research and Collaboration; name: Canadian Cancer Society, award: 701582; name: the Sarcoma Cancer Foundation of Canada Beth England's Sarcoma Research Fund; name: Pedal for Home Impact Grant of the Canadian Cancer Society, award: 705615; name: Washington University in St. Louis School of Medicine MSTP training grant, award: 5T32GM007200; name: National Cancer Institute, award: R01 CA163764; name: Washington University Surgical Oncology Training Gran, award: T32CA009621; DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: R01 DK104998; DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases, award: F30 DK127845; name: University of Iowa Medical Scientist Training Program, award: T32TGM007337
- Language
- English
- Date published
- 04/29/2022
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297499202771
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