Research Papers:
Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation
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Abstract
Hua Yang1, Harshani R. Lawrence3, Aslamuzzaman Kazi1, Harsukh Gevariya1, Ronil Patel1, Yunting Luo3, Uwe Rix1,2,4, Ernst Schonbrunn1,2,4, Nicholas J. Lawrence1,2,4, Said M. Sebti1,2,4
1 Drug Discovery Department, University of South Florida, Tampa, FL, USA.
2 Chemical Biology and Molecular Medicine Program, University of South Florida, Tampa, FL, USA.
3 Chemical Biology Core, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.
4 Departments of Molecular Medicine and Oncologic Sciences, University of South Florida, Tampa, FL, USA.
Correspondence:
Saïd M. Sebti, e-mail: said.sebti@moffitt.org
Conflict of Interests The Authors have no conflict of interests.
Received: November 20, 2013 Accepted: March 19, 2014 Published: March 22, 2014
ABSTRACT
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.
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