Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis

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.

NEK2 serves as a prognostic biomarker for hepatocellular carcinoma

“…Previous studies suggested that the overexpression of NEK2 promotes activation of AKT, a potent and critical oncogene for a variety of malignancies (26,27). Moreover, the PI3K/AKT signaling pathway plays an important role in upregulating MMP expression (28).…”

“…Previous studies suggested that NEK2 may be involved in tumor progression through the influence of other tumor pathways. The elevation of NEK2 contributes to the activation of the PI3K/AKT signaling pathway, a potent and critical oncogene for a variety of malignancies (26,27). Moreover, the PI3K/AKT signaling pathway plays an important role in upregulating MMP expression (28), and aberrant AKT signaling could promote cell proliferation in HCC cells (37).…”

Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism

“…As a cell cycle-regulated serine/threonine kinase, Nek2A may undergo autophosphorylation, because the phosphoamino acid analysis of labeled Nek2 protein showed predominant phosphoserine and minor phosphothreonine. Studies in Drosophila melanogaster and human diseases of Nek2 illustrated that overexpression of Nek2 correlated to activation of the Akt and JNK pathways, as well as upregulation of Wnt signaling, which are highly conserved in multiple species and involved in cellular growth and survival [40,41]. Therefore, Nek2 has been emerged as an important oncogene due to its regulatory role in mitosis and cancer related signaling pathways [41][42][43][44].…”

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

“…A recent study reported that NEK2 silencing by shRNAs reduces tumor cell progression by interference with chromosomal segregation in human breast cancer cell lines in vitro and in fat pad xenograft mouse models, leading to aneuploidy and subsequent cell death (35). Another study indicated that in human lung and colorectal cancer cell lines, NEK2 plays a critical role in the subcellular transfer of β-catenin from the plasma membrane to the cytoplasm and the nucleus, leading to an invasive cellular phenotype in vitro and in vivo (11,36). Our data indicated that NEK2 expression was elevated in the stem cell fraction in GBM and was essential for GSC stemness in vitro and in vivo.…”