Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress

Emma E. Croushore; Stacia L. Koppenhafer; Kelli L. Goss; Elizabeth L. Geary; David J. Gordon

doi:10.1158/2767-9764.CRC-23-0268

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Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress

Journal article

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Peer reviewed

Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress

Emma E. Croushore, Stacia L. Koppenhafer, Kelli L. Goss, Elizabeth L. Geary and David J. Gordon

Cancer research communications, Vol.3(8), pp.1580-1593

08/17/2023

DOI: 10.1158/2767-9764.CRC-23-0268

PMCID: PMC10434289

PMID: 37599787

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Abstract

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in the synthesis of deoxyribonucleosides and is required for DNA replication. Multiple types of cancer, including Ewing sarcoma tumors, are sensitive to RNR inhibitors or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. However, the polypharmacology and off-target effects of RNR inhibitors have complicated the identification of the mechanisms that regulate sensitivity and resistance to this class of drugs. Consequently, we used a conditional knockout (CRISPR/Cas9) and rescue approach to target RRM1 in Ewing sarcoma cells and identified that loss of the RRM1 protein results in the upregulation of the expression of multiple members of the activator protein-1 (AP-1) transcription factor complex, including c-Jun and c-Fos, and downregulation of c-Myc. Notably, overexpression of c-Jun and c-Fos in Ewing sarcoma cells is sufficient to inhibit cell growth and downregulate the expression of the c-Myc oncogene. We also identified that the upregulation of AP-1 is mediated, in part, by SLFN11, which is a replication stress response protein that is expressed at high levels in Ewing sarcoma. In addition, small-molecule inhibitors of RNR, including gemcitabine, and histone deacetylase inhibitors, which reduce the level of the RRM1 protein, also activate AP-1 signaling and downregulate the level of c-Myc in Ewing sarcoma. Overall, these results provide novel insight into the critical pathways activated by loss of RNR activity and the mechanisms of action of inhibitors of RNR.

Cell Cycle

Dna Damage And Repair

Drug Targets

Sarcomas

Details

Title: Subtitle: Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress
Creators: Emma E. Croushore - University of Iowa
Stacia L. Koppenhafer - University of Iowa
Kelli L. Goss - University of Iowa
Elizabeth L. Geary - University of Iowa
David J. Gordon - University of Iowa
Resource Type: Journal article
Publication Details: Cancer research communications, Vol.3(8), pp.1580-1593
DOI: 10.1158/2767-9764.CRC-23-0268
PMID: 37599787
PMCID: PMC10434289
NLM abbreviation: Cancer Res Commun
eISSN: 2767-9764
Publisher: American Association for Cancer Research
Grant note: ; R37-CA217910 / ; NCI P30CA086862 / ;
Alternative title: Inhibition of RNR Activates AP-1 Signaling in Ewing Sarcoma
Language: English
Date published: 08/17/2023
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics; Hematology/Oncology
Record Identifier: 9984455539702771

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