Abstract
Centrosomal kinase Nek2 is overexpressed in different cancers, yet how it contributes toward tumorigenesis remains poorly understood. dNek2 overexpression in a Drosophila melanogaster model led to upregulation of Drosophila Wnt ortholog wingless (Wg), and alteration of cell migration markers—Rho1, Rac1 and E-cadherin (Ecad)—resulting in changes in cell shape and tissue morphogenesis. dNek2 overexpression cooperated with receptor tyrosine kinase and mitogen-activated protein kinase signaling to upregulate activated Akt, Diap1, Mmp1 and Wg protein to promote local invasion, distant seeding and metastasis. In tumor cell injection assays, dNek2 cooperated with Ras and Src signaling to promote aggressive colonization of tumors into different adult fly tissues. Inhibition of the PI3K pathway suppressed the cooperation of dNek2 with other growth pathways. Consistent with our fly studies, overexpression of human Nek2 in A549 lung adenocarcinoma and HEK293T cells led to activation of the Akt pathway and increase in β-catenin protein levels. Our computational approach identified a class of Nek2-inhibitory compounds and a novel drug-like pharmacophore that reversed the Nek2 overexpression phenotypes in flies and human cells. Our finding posits a novel role for Nek2 in promoting metastasis in addition to its currently defined role in promoting chromosomal instability. It provides a rationale for the selective advantage of centrosome amplification in cancer.
Highlights
Centrosomal kinases are important regulators of cell division
Uptake of Nek[2] siRNA into the tumor significantly reduced tumor size, suggesting Nek[2] inhibition can counter tumor progression in vivo.[6]. These findings suggest that Nek[2] regulates tumor progression in vivo and that Nek[2] inhibition could be useful for developing anti-cancer therapeutics
By proceeding from virtual screening, to in vitro testing, to using notum/scutellum can lead to similar tissue defects, e.g., activation our fly model, we rapidly identified drug-like compounds most of the Jun N-terminal kinase (Jnk) pathway.[17] dNek[2] overoptimal for Nek[2] inhibition in vivo
Summary
Centrosomal kinases are important regulators of cell division They control key processes such as centrosome cycle, kinetochore– microtubule attachment, spindle checkpoint/assembly, chromosome condensation and cytokinesis. Uncontrolled activity of these kinases can lead to spindle abnormalities, centrosome fragmentation, premature centriole splitting, cytokinesis defects, multinucleation, supernumerary centrosomes and chromosome segregation errors. These cellular phenotypes, referred to as chromosomal instability (CIN), are frequently observed in transformed cells indicating that overexpression of mitotic kinases might drive tumor progression in vivo by promoting CIN.[1,2] Yet a clear notion of the mechanism by which these kinases contribute to tumorigenesis remains elusive. Like the other centrosomal kinases, the role of Nek[2] in tumor progression remains unclear
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