The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

Abstract Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene...

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Autores principales:	Kinjal Shah, Mehreen Ahmed, Julhash U. Kazi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/8d171ef063c246f09213d55170975b31
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spelling	oai:doaj.org-article:8d171ef063c246f09213d55170975b312021-12-02T14:39:37ZThe Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia10.1038/s41698-021-00148-52397-768Xhttps://doaj.org/article/8d171ef063c246f09213d55170975b312021-02-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00148-5https://doaj.org/toc/2397-768XAbstract Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene signature to develop a deep learning model that can predict dexamethasone sensitivity. By combining gene expression data from cell lines and patients with acute lymphoblastic leukemia, we observed that the model is useful for the classification of patients. Predicted samples have been used to detect deregulated pathways that lead to dexamethasone resistance. Gene set enrichment analysis, peptide substrate-based kinase profiling assay, and western blot analysis identified Aurora kinase, S6K, p38, and β-catenin as key signaling proteins involved in dexamethasone resistance. Deep learning-enabled drug synergy prediction followed by in vitro drug synergy analysis identified kinase inhibitors against Aurora kinase, JAK, S6K, and mTOR that displayed synergy with dexamethasone. Combining pathway enrichment, kinase regulation, and kinase inhibition data, we propose that Aurora kinase or its several direct or indirect downstream kinase effectors such as mTOR, S6K, p38, and JAK may be involved in β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β. Collectively, our data suggest that activation of the Aurora kinase/β-catenin axis during dexamethasone treatment may contribute to cell survival signaling which is possibly maintained in patients who are resistant to dexamethasone.Kinjal ShahMehreen AhmedJulhash U. KaziNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kinjal Shah Mehreen Ahmed Julhash U. Kazi The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
description	Abstract Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene signature to develop a deep learning model that can predict dexamethasone sensitivity. By combining gene expression data from cell lines and patients with acute lymphoblastic leukemia, we observed that the model is useful for the classification of patients. Predicted samples have been used to detect deregulated pathways that lead to dexamethasone resistance. Gene set enrichment analysis, peptide substrate-based kinase profiling assay, and western blot analysis identified Aurora kinase, S6K, p38, and β-catenin as key signaling proteins involved in dexamethasone resistance. Deep learning-enabled drug synergy prediction followed by in vitro drug synergy analysis identified kinase inhibitors against Aurora kinase, JAK, S6K, and mTOR that displayed synergy with dexamethasone. Combining pathway enrichment, kinase regulation, and kinase inhibition data, we propose that Aurora kinase or its several direct or indirect downstream kinase effectors such as mTOR, S6K, p38, and JAK may be involved in β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β. Collectively, our data suggest that activation of the Aurora kinase/β-catenin axis during dexamethasone treatment may contribute to cell survival signaling which is possibly maintained in patients who are resistant to dexamethasone.
format	article
author	Kinjal Shah Mehreen Ahmed Julhash U. Kazi
author_facet	Kinjal Shah Mehreen Ahmed Julhash U. Kazi
author_sort	Kinjal Shah
title	The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
title_short	The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
title_full	The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
title_fullStr	The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
title_full_unstemmed	The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
title_sort	aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8d171ef063c246f09213d55170975b31
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The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

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