Article ; Online: Activator Protein-1 (AP-1) Signaling Inhibits the Growth of Ewing Sarcoma Cells in Response to DNA Replication Stress.
Cancer research communications
2023 Volume 3, Issue 8, Page(s) 1580–1593
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 ... ...
| 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. Significance: RNR is the rate-limiting enzyme in the synthesis of deoxyribonucleotides. Although RNR is the target of multiple chemotherapy drugs, polypharmacology and off-target effects have complicated the identification of the precise mechanism of action of these drugs. In this work, using a knockout-rescue approach, we identified that inhibition of RNR upregulates AP-1 signaling and downregulates the level of c-Myc in Ewing sarcoma tumors. |
|---|---|
| MeSH term(s) | Humans ; Sarcoma, Ewing/drug therapy ; Transcription Factor AP-1/genetics ; Neuroectodermal Tumors, Primitive, Peripheral ; Signal Transduction/genetics ; Proto-Oncogene Proteins c-fos/genetics ; Ribonucleotide Reductases ; Craniocerebral Trauma ; DNA Replication/genetics ; Nuclear Proteins |
| Chemical Substances | Transcription Factor AP-1 ; Proto-Oncogene Proteins c-fos ; Ribonucleotide Reductases (EC 1.17.4.-) ; SLFN11 protein, human ; Nuclear Proteins |
| Language | English |
| Publishing date | 2023-08-17 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ISSN | 2767-9764 |
| ISSN (online) | 2767-9764 |
| DOI | 10.1158/2767-9764.CRC-23-0268 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.
Inter-library loan at ZB MED
Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.