NIMA-related Kinase 2 Expression Research Articles

Deguelin inhibits epithelial-to-mesenchymal transition and metastasis of human non-small cell lung cancer cells by regulating NIMA-related kinase 2.

BackgroundNon‐small cell lung cancer is a lethal malignancy with a high mortality rate. Deguelin displays an anti‐tumor effect and inhibits metastasis in various cancers. The aberrant expression of NIMA‐related kinase 2 (NEK2) indicates poor prognosis and induces epithelial‐to‐mesenchymal transition (EMT) and metastasis processes. However, the underlying mechanism between deguelin and NEK2 has remained elusive.Methods NSCLC cell lines were treated with deguelin. Wound‐healing and invasion assays were applied to study the inhibitory effect of deguelin on NSCLC cells. EMT markers, E‐cadherin and Vimentin, were also detected by Western blot. NEK2 protein and messenger RNA expression levels were evaluated when NSCLC cells were treated with different concentrations of deguelin. The effect of NEK2 on NSCLC cell metastasis was evaluated through NEK2 knockdown. To investigate whether deguelin induced EMT by regulating NEK2, we overexpressed NEK2 in both NCI‐H520 and SK‐MES‐1 cell lines, and then used real time‐PCR to study the E‐cadherin and Vimentin messenger RNA expression in both NSCLC cells.ResultsDeguelin inhibited migration and invasion processes in NSCLC cell lines and decreased NEK2 expression in a concentration‐dependent manner. Furthermore, NEK2 knockdown inhibited NSCLC cell migration and invasion. Finally, overexpressing NEK2 in NCI‐H520 and SK‐MES‐1 cells could restore the inhibition of metastasis induced by deguelin.ConclusionsDeguelin could inhibit EMT and metastasis, while overexpression of NEK2 promotes these processes. Deguelin could decrease NEK2 expression, while NEK2 overexpression could restore deguelin‐induced inhibition of metastasis.

Overexpression of NIMA-related kinase 2 is associated with poor prognoses in malignant glioma.

Eleated expression of NIMA-related kinase 2 (NEK2) was frequently observed in a variety of malignant cancers, and it appears to be involved in the initiation, maintenance, progression, metastasis of cancer and is positively associated with poor prognosis. We sought to investigate NEK2 expression and its predictive roles in malignant gliomas, and study the correlation of NEK2 protein expression with proliferation, clinical parameters, overall survival and some other parameters. We investigate NEK2 protein expression in 99 samples of malignant gliomas, including 35 WHO grade II, 22 grade III, and 42 grade IV gliomas, by immunohistochemistry and western blot (n = 50). We then made correlative analysis of protein overexpression using the Kaplan-Meier method, Log rank test, and Cox proportional-hazards model analysis. NEK2 protein was overexpressed in malignant gliomas, but not in normal brain tissues. Overexpression of NEK2 correlated with malignancy, proliferation and adverse overall survival in gliomas. Moreover, chemotherapy, resection extent and WHO grade also correlate with overall survival in gliomas. However, within WHO grade II glioma subgroup, NEK2 overexpression showed no impact on overall survival. The present study firstly reveals that NEK2 protein is widely overexpressed in gliomas. NEK2 overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki-67) and prognosis in malignant gliomas. NEK2 is a potential gene therapy target and prognostic indicator.

Molecular modeling and docking of small molecule inhibitors against NEK2.

Aberrant expression of NEK2 (NIMA-related kinase 2) is indicated in a wide variety of human cancers. NEK2 is highly correlated to multi drug resistance by activating drug efflux activity. Identification of new small molecule inhibitors targeted against NEK2 therefore, facilitates to increase drug sensitivity of cancer cells, by stabilizing drug influx and minimizes the dose of therapeutic drug. Our work investigates to screen for optimal small molecule inhibitors against NEK2. In this study, we used a computational approach by modeling NEK2 protein using I-TASSER (Iterative Threading ASSEmbly Refinement) software. The modeled structure was subjected to protein preparation wizard; to add hydrogens and to optimize the protonation states of His, Gln and Asn residues. Active site of the modeled protein was identified using SiteMap tool of Schrodinger package. We further carried out docking studies by means of Glide, with various ligands downloaded from EDULISS database. Based on glide score, potential ligands were screened and their interaction with NEK2 was identified. The best hits were further screened for Lipinski’s rule for drug-likeliness, bioactivity scoring and ADME properties. Thus, we report two (didemethylchlorpromazine and 2-[5-fluoro-1Hindol- 3-yl] propan-1-amine) compounds that have successfully satisfied all in silico parameters, necessitating further in vitro and in vivo studies.

Overexpression of NIMA-related kinase 2 is associated with progression and poor prognosis of prostate cancer.

BackgroundThe NIMA-related kinase 2 (NEK2) is a serine/threonine kinase that is involved in regulation of centrosome duplication and spindle assembly during mitosis. Dysregulation of these processes causes chromosome instability and aneuploidy, which are hallmark changes of many solid tumors. However, whether aberrant expression of NEK2 is associated with outcome of prostate cancer (PCa) patients remains to be determined.MethodsExpression of NEK2 in human PCa cells and primary PCa tissues was assessed by quantitative RT-PCR. Expression of NEK2 in human PCa cells was depleted with siRNA. Effects of the depletion on cell proliferation, survival, and tumorigenicity were assessed both in vitro with cell cultures and in vivo with subcutaneous implantation of xenografts. In silico analyses of the online Taylor dataset were carried out to determine whether the expression level of NEK2 correlated with the clinicopathological characteristics of prostate cancer.ResultsCompared with benign human prostatic epithelial cells and tissues, the expression of NEK2 was elevated in human PCa cells and primary PCa tissues. Depleting NEK2 expression inhibited human PCa cell proliferation in vitro and xenograft growth in vivo. Expression level of NEK2 in PCa positively correlated with the Gleason score and pathologic stage of the patient.ConclusionThe results suggest that overexpression of NEK2 has the potential to serve as a biomarker for PCa prognosis. Further validation with large sample pool is warrant.

Up-regulation of NEK2 by MicroRNA-128 Methylation is Associated with Poor Prognosis in Colorectal Cancer

NIMA-related kinase 2 (NEK2), an enzyme involved in the development and progression of cancer, is abnormally expressed in a wide variety of human cancers, including colorectal cancer (CRC), and is known to have roles in cell division and mitotic regulation through centrosome splitting. We investigated the clinical significance of NEK2 in CRC. In particular, we examined miR-128 expression, which is thought to target NEK2. We measured NEK2 mRNA and miR-128 levels in clinical samples by quantitative reverse transcription real-time PCR and analyzed the associations between NEK2 levels, miR-128 levels, clinicopathological factors, and prognoses. Furthermore, we performed in vitro assays using a pre-miR-128 precursor and conducted miR-128 methylation analyses. MiR-128 inhibited NEK2 expression and cancer cell proliferation via cell cycle arrest. Moreover, miR-128 was silenced by DNA methylation. Increased NEK2 expression was associated with serosal invasion, lymphatic invasion, and peritoneal dissemination. Patients with high NEK2 expression also had significantly poorer prognoses. Multivariate analysis indicated that high NEK2 expression was an independent prognostic factor for survival. Patients with high miR-128 expression had significantly lower NEK2 expression and lower recurrence rates than those with low miR-128 expression. NEK2 may be an independent prognostic factor for CRC and was regulated by miR-128, a microRNA that was subjected to epigenetic regulation. Thus, this miR-128/NEK2 pathway may be a prospective therapeutic target for patients with CRC.