title: Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation.
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.
authors.affiliation: Drug Discovery Department, Chemical Biology and Molecular Medicine Program, Chemical Biology Core Moffitt Cancer Center and Research Institute.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Harsukh
authors.initials: H
authors.lastname: Gevariya
authors.forename: Ronil
authors.initials: R
authors.lastname: Patel
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Ernst
authors.initials: E
authors.lastname: Schonbrunn
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C576917:AURKA protein, human; D064096:Aurora Kinase A