Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.
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 Ew...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0253170 |
| _version_ | 1818401105303830528 |
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| author | Handan Sevim Haydar Çelik Levent Düşünceli Ceyda S Ceyhan Anna Molotkova Kay Nakazawa Garrett T Graham Jeffrey R Petro Jeffrey A Toretsky Aykut Üren |
| author_facet | Handan Sevim Haydar Çelik Levent Düşünceli Ceyda S Ceyhan Anna Molotkova Kay Nakazawa Garrett T Graham Jeffrey R Petro Jeffrey A Toretsky Aykut Üren |
| author_sort | Handan Sevim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T07:47:11Z |
| format | Article |
| id | doaj.art-e9183073007d4d23ac98366b8bb127d1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T07:47:11Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e9183073007d4d23ac98366b8bb127d12022-12-21T23:10:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01166e025317010.1371/journal.pone.0253170Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.Handan SevimHaydar ÇelikLevent DüşünceliCeyda S CeyhanAnna MolotkovaKay NakazawaGarrett T GrahamJeffrey R PetroJeffrey A ToretskyAykut ÜrenClofarabine, 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.https://doi.org/10.1371/journal.pone.0253170 |
| spellingShingle | Handan Sevim Haydar Çelik Levent Düşünceli Ceyda S Ceyhan Anna Molotkova Kay Nakazawa Garrett T Graham Jeffrey R Petro Jeffrey A Toretsky Aykut Üren Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. PLoS ONE |
| title | Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. |
| title_full | Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. |
| title_fullStr | Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. |
| title_full_unstemmed | Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. |
| title_short | Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. |
| title_sort | clofarabine induces erk msk creb activation through inhibiting cd99 on ewing sarcoma cells |
| url | https://doi.org/10.1371/journal.pone.0253170 |
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