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Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation
Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furth...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102782/ https://www.ncbi.nlm.nih.gov/pubmed/24930769 |
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author | Yang, Hua Lawrence, Harshani R. Kazi, Aslamuzzaman Gevariya, Harsukh Patel, Ronil Luo, Yunting Rix, Uwe Schonbrunn, Ernst Lawrence, Nicholas J. Sebti, Said M. |
author_facet | Yang, Hua Lawrence, Harshani R. Kazi, Aslamuzzaman Gevariya, Harsukh Patel, Ronil Luo, Yunting Rix, Uwe Schonbrunn, Ernst Lawrence, Nicholas J. Sebti, Said M. |
author_sort | Yang, Hua |
collection | PubMed |
description | Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and –independent growth and invasion as well as at inducing apoptosis. Importantly, we have developed dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, AJI-100 caused regression of human tumor xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each kinase alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents. |
format | Online Article Text |
id | pubmed-4102782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-41027822014-07-23 Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation Yang, Hua Lawrence, Harshani R. Kazi, Aslamuzzaman Gevariya, Harsukh Patel, Ronil Luo, Yunting Rix, Uwe Schonbrunn, Ernst Lawrence, Nicholas J. Sebti, Said M. Oncotarget Research Paper Aurora A and JAK2 kinases are involved in cell division and tumor cell survival, respectively. Here we demonstrate that ectopic expression of Aurora A and JAK2 together is more effective than each alone at inducing non-transformed cells to grow in an anchorage-independent manner and to invade. Furthermore, siRNA silencing or pharmacological inhibition of Aurora A and JAK2 with Alisertib and Ruxolitinib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and –independent growth and invasion as well as at inducing apoptosis. Importantly, we have developed dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, AJI-100 caused regression of human tumor xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each kinase alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents. Impact Journals LLC 2014-03-22 /pmc/articles/PMC4102782/ /pubmed/24930769 Text en Copyright: © 2014 Yang et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yang, Hua Lawrence, Harshani R. Kazi, Aslamuzzaman Gevariya, Harsukh Patel, Ronil Luo, Yunting Rix, Uwe Schonbrunn, Ernst Lawrence, Nicholas J. Sebti, Said M. Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title | Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title_full | Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title_fullStr | Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title_full_unstemmed | Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title_short | Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation |
title_sort | dual aurora a and jak2 kinase blockade effectively suppresses malignant transformation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102782/ https://www.ncbi.nlm.nih.gov/pubmed/24930769 |
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