Targeting NEK2 as a promising therapeutic approach for cancer treatment

Fang, Yanfen; Zhang, Xiongwen

doi:10.1080/15384101.2016.1152430

Cited by 111 publications

(117 citation statements)

References 96 publications

(145 reference statements)

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“…NEK2 overexpression is associated with tumorigenensis, tumor progression, drug resistance and predicts poor prognosis [18, 19]. Several preclinical studies using RNA interference targeting NEK2 have shown the efficient anti-tumor effect against different type of cancers.…”

Section: Introductionmentioning

confidence: 99%

Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity

Fang

Kong

et al. 2016

Oncotarget

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NEK2 is a conserved mitotic regulator critical for cell cycle progression. Aberrant expression of NEK2 has been found in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. In the present study, we have identified a novel compound MBM-5, which was found to bind to NEK2 with high affinity by docking simulations study. MBM-5 potently inhibited NEK2 kinase activity in vitro in a concentration-dependent manner. MBM-5 also suppressed cellular NEK2 kinase activity, as evidenced by the decreased phosphorylation of its substrate Hec1 on S165 in a concentration- and time-dependent manner. This inhibition impeded mitotic progression by inducing chromosome segregation defects and cytokinesis failure; therefore leading to accumulation of cells with ≥4N DNA content, which finally underwent apoptosis. More importantly, MBM-5 treatment effectively suppressed the tumor growth of human gastric and colorectal cancer cells xenografts. Taken together, we demonstrated that MBM-5 effectively inhibited the kinase activity of NEK2 and showed a potential application in anti-cancer treatment regimens.

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Section: Introductionmentioning

confidence: 99%

Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity

Fang

Kong

et al. 2016

Oncotarget

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“…Emerging evidence has documented that NEK2 is an important carcinoma biomarker for prognosis and serves as a therapeutic target . A recent report showed that NEK2 ectopic expression not only promotes hepatocellular cancer progression, but also activates drug resistance independent of protein phosphatase‐1/protein kinase B and Wnt/β‐catenin pathway activation .…”

Section: Discussionmentioning

confidence: 99%

“…In a variety of cancers, NEK2 is aberrantly expressed and is associated with drug resistance and poor prognosis . Recent studies have indicated that NEK2 represents a promising therapeutic target for cancer treatment . For instance, in a previous study, miR‐128 played an essential role in inhibiting colorectal cancer cell proliferation by regulating NEK2 .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐128 promotes apoptosis in lung cancer by directly targeting NIMA‐related kinase 2

et al. 2017

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BackgroundMicroRNA‐128 (miR‐128) serves as a regulator by inducing cancer cell apoptosis, differentiation, the epithelial‐to‐mesenchymal transition process, and tumor growth by mediating different targets. NIMA‐related kinase 2 (NEK2) is aberrantly expressed in lung cancer. The miR‐128/NEK2 pathway has been reported to predict prognosis in colorectal cancer; however, the determination of a relationship between miR‐128 and NEK2 in lung cancer has remained elusive. We explored the association between miR‐128 and NEK2 in lung cancer.MethodsMiR‐128 and NEK2 expression were examined in 15 lung cancer tissues by real time‐PCR. Lung cancer SK‐MES‐1 cells were transfected with miR‐128 mimic, an inhibitor or a negative control. MiR‐128 and NEK2 expression levels were detected using quantitative real time‐PCR and Western blot. SK‐MES‐1 cell apoptosis was performed by flow cytometry.ResultsCompared to adjacent non‐tumor tissues, miR‐128 was downregulated and NEK2 was upregulated in 15 lung cancer tissues. Lung cancer SK‐MES‐1 cells transfected with miR‐128 mimic induced a higher apoptotic rate than those transfected with the negative control. Dual luciferase assay further confirmed that NEK2 was a direct target of miR‐128 in lung cancer, and transfection with miR‐128 mimic could decrease the NEK2 protein level while the miR‐128 inhibitor increased NEK2 expression. Finally, the apoptotic effect of lung cancer cells induced by miR‐128 mimic could be reversed by NEK2 overexpression.Conclusions NEK2 was regulated by miR‐128 in lung cancer and miR‐128 induced lung cancer cell apoptosis by mediating NEK2 expression.

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“…It is interesting to note that many SAC components that are activated by incomplete attachment of microtubules to kinetochores, and kinetochore factors (BUB1, CENPL, CEP152, NUF2, SPC24, SPC25, NEK2, INCENP, SGO1L, MLF1IP, CASC5, NDC80, and ASPM), are all highly overexpressed in MDR canines ( Supplemental Tables S2 and S3). Elevated expression of SAC and kinetochore components (NCAPG, NCAPG, SKA3, AURKB, NEK2) is associated with cancer [50][51][52][53][54][55], and is consistent with APC impairment.…”

Section: To Normal Controlsmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

Aranson

MacDonald-Dickinson

Davies

et al. 2020

Preprint

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Like humans, canine companions spontaneously develop lymphomas that are treated by a cocktail of chemotherapy drugs. However, canines have high rates of developing multiple drug resistance (MDR), shortened clinical timelines and easy tumor accessibility, making them excellent models to study MDR mechanisms. Previously, we used in vitro cell models to demonstrate that metformin resensitized MDR cells to chemotherapy and prevented MDR development. Here, we used metformin to understand the in vivo molecular mechanisms regulating MDR development and reversal. Metformin was added to chemotherapy in MDR canines, reducing MDR biomarkers within all tumors tested, with one canine entering remission after prior repeated relapses. We employed microarray analyses to identify molecular networks involved in MDR development and the impact of metformin treatement. Tumor sampling throughout entry to remission and subsequent relapse allowed correlation of gene expression profiles to MDR tumor behavior. We discovered that the Anaphase Promoting Complex (APC), a ubiquitin-ligase regulating cell cycle progression, was impaired in MDR samples. In vitro tests demonstrated that APC activation resensitized MDR cells to chemotherapy. The companion canine, therefore, is a powerful translational MDR model that has revealed the APC as an underlying cellular mechanism associated with treatment resistance, and a novel potential therapeutic target.

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Targeting NEK2 as a promising therapeutic approach for cancer treatment

Cited by 111 publications

References 96 publications

Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity

Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity

MicroRNA‐128 promotes apoptosis in lung cancer by directly targeting NIMA‐related kinase 2

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

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