Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells
| Autor: | Anna Molotkova, Ceyda S. Ceyhan, Jeffrey R. Petro, Aykut Üren, Kay Nakazawa, Garrett T. Graham, Jeffrey A. Toretsky, Handan Sevim, Haydar Çelik, Levent Dusunceli |
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| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Cell Membranes Cancer Treatment Apoptosis Biochemistry Medicine and Health Sciences Clofarabine Post-Translational Modification Phosphorylation Multidisciplinary Cell Death biology Chemistry Deoxycytidine kinase CREB-Binding Protein Precipitation Techniques Nucleic acids Oncology Cell Processes Medicine Cellular Structures and Organelles Signal transduction Research Article Signal Transduction medicine.drug Antimetabolites Antineoplastic Programmed cell death MAP Kinase Signaling System Nucleic acid synthesis Science Immunology Blotting Western Sarcoma Ewing 12E7 Antigen CREB Ribosomal Protein S6 Kinases 90-kDa Antibody Therapy Cell Line Tumor Genetics medicine Immunoprecipitation Humans Chemical synthesis DNA synthesis Biology and Life Sciences Proteins Membrane Proteins Cell Biology DNA Research and analysis methods Biosynthetic techniques biology.protein Cancer research Clinical Immunology Clinical Medicine |
| Zdroj: | PLoS ONE, Vol 16, Iss 6, p e0253170 (2021) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Clofarabine, an FDA approved purine analog, is used in the treatment of relapsed or refractory acute lymphoblastic leukemia. Clofarabine acts by inhibiting DNA synthesis. We demonstrated that clofarabine may have a novel function though inhibiting CD99, a transmembrane protein highly expressed on Ewing Sarcoma (ES) cells. CD99 is a validated target in ES whose inhibition may lead to a high therapeutic index for patients. Here we present additional data to support the hypothesis that clofarabine acts on CD99 and regulates key signaling pathways in ES. Cellular thermal shift assay indicated a direct interaction between clofarabine and CD99 in ES cell lysates. Clofarabine induced ES cell death does not require clofarabine’s conversion to its active form by deoxycytidine kinase. A phosphokinase array screen with clofarabine and a CD99 blocking antibody identified alterations in signaling pathways. CD99 inhibition with clofarabine in ES cells caused rapid and sustained phosphorylation of ERK, MSK, and CREB. However, activation of this pathway did not correlate with clofarabine induced ES cell death. In summary, we demonstrated that clofarabine may activate ERK, MSK, and CREB phosphorylation through CD99 within minutes, however this paradoxical activation and subsequent ES cell death requires additional investigation. |
| Databáze: | OpenAIRE |
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