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...

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Autores principales:	Handan Sevim, Haydar Çelik, Levent Düşünceli, Ceyda S Ceyhan, Anna Molotkova, Kay Nakazawa, Garrett T Graham, Jeffrey R Petro, Jeffrey A Toretsky, Aykut Üren
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e9183073007d4d23ac98366b8bb127d1
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spelling	oai:doaj.org-article:e9183073007d4d23ac98366b8bb127d12021-12-02T20:10:36ZClofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.1932-620310.1371/journal.pone.0253170https://doaj.org/article/e9183073007d4d23ac98366b8bb127d12021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253170https://doaj.org/toc/1932-6203Clofarabine, 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.Handan SevimHaydar ÇelikLevent DüşünceliCeyda S CeyhanAnna MolotkovaKay NakazawaGarrett T GrahamJeffrey R PetroJeffrey A ToretskyAykut ÜrenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253170 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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.
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.
format	article
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
title	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_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_sort	clofarabine induces erk/msk/creb activation through inhibiting cd99 on ewing sarcoma cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/e9183073007d4d23ac98366b8bb127d1
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Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.

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