Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death

Park, Soo‐Young; Jo, Doo Sin; Jo, Se-Young; Shin, Dong Woon; Shim, Sangmi; Jo, Yoon Kyung; Shin, Ji Hyun; Ha, Ye Jin; Jeong, Seong‐Yun; Hwang, Jung Jin; Kim, Young Sam; Suh, Young‐Ah; Chang, Jong Wook; Kim, Jin Cheon; Cho, Dong‐Hyung

doi:10.18632/oncotarget.11781

Cited by 14 publications

(18 citation statements)

References 41 publications

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“…NEK4 is one of the Nek family members and overexpressed in lung cancer and colorectal cancer . Nek protein family includes 11 subtypes and belongs to serine‐threonine kinases .…”

Section: Discussionmentioning

confidence: 99%

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NEK4 kinase regulates EMT to promote lung cancer metastasis

Ding

Zhang

Zhi

et al. 2018

J Cellular Molecular Medi

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Epithelial‐to‐mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E‐cadherin promoter‐luciferase reporter vectors. NIMA‐related kinase‐4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion‐related proteins such as E‐cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E‐cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4‐knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis.

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“…NEK4 is one of the Nek family members and overexpressed in lung cancer and colorectal cancer . Nek protein family includes 11 subtypes and belongs to serine‐threonine kinases .…”

Section: Discussionmentioning

confidence: 99%

“…NEK4 is one of the Nek family members and overexpressed in lung cancer and colorectal cancer. 18,19 Nek protein family includes 11 subtypes and belongs to serine-threonine kinases. 20 The Nek proteins share substantial homology at the amino terminal domain but exhibit variable homology at the carboxyl region.…”

Section: Discussionmentioning

confidence: 99%

NEK4 kinase regulates EMT to promote lung cancer metastasis

Ding

Zhang

Zhi

et al. 2018

J Cellular Molecular Medi

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“…Nowadays, a number of PLK1-inhibitors are under investigation for their use as targeted therapies against cancer [ 102 ]. The potential use of NEK2 inhibition as a targeted treatment against different types of malignancies is also under study, with promising expectations [ 106 , 182 , 183 , 184 , 185 ], as in vitro NEK2 inhibition induce breast cancer cells aneuploidy and cell cycle arrest, especially in TNBC [ 107 ].…”

Section: Protein Kinase Targets For Breast Cancer Treatmentmentioning

confidence: 99%

Protein Kinase Targets in Breast Cancer

García-Aranda

Redondo

2017

IJMS

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With 1.67 million new cases and 522,000 deaths in the year 2012, breast cancer is the most common type of diagnosed malignancy and the second leading cause of cancer death in women around the world. Despite the success of screening programs and the development of adjuvant therapies, a significant percentage of breast cancer patients will suffer a metastatic disease that, to this day, remains incurable and justifies the research of new therapies to improve their life expectancy. Among the new therapies that have been developed in recent years, the emergence of targeted therapies has been a milestone in the fight against cancer. Over the past decade, many studies have shown a causal role of protein kinase dysregulations or mutations in different human diseases, including cancer. Along these lines, cancer research has demonstrated a key role of many protein kinases during human tumorigenesis and cancer progression, turning these molecules into valid candidates for new targeted therapies. The subsequent discovery and introduction in 2001 of the kinase inhibitor imatinib, as a targeted treatment for chronic myelogenous leukemia, revolutionized cancer genetic pathways research, and lead to the development of multiple small-molecule kinase inhibitors against various malignancies, including breast cancer. In this review, we analyze studies published to date about novel small-molecule kinase inhibitors and evaluate if they would be useful to develop new treatment strategies for breast cancer patients.

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“…Another study declared that NEK4 inhibition potentiates TRAIL-induced cell death in TRAIL (tumor necrosis factor-related apoptosis inducing ligand)-resistant cancer cells. It was found that TRAIL-induced cell death in NEK4 knockdown cells was completely blocked by a pan caspase inhibitor, Z-VAD, but not by the necrosis inhibitor, necrostatin-1, or by the autophagy inhibitor, Bafilomycin A1 [ 51 ]. It suggests that NEK4 inhibition mediated autophagy induction does not contribute to these types of cell death.…”

Section: Kinases Originally Involved In Mitotic Regulation Are Shomentioning

confidence: 99%

Kinases Involved in Both Autophagy and Mitosis

Zhang

2017

IJMS

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Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations.

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Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death

Cited by 14 publications

References 41 publications

NEK4 kinase regulates EMT to promote lung cancer metastasis

NEK4 kinase regulates EMT to promote lung cancer metastasis

Protein Kinase Targets in Breast Cancer

Kinases Involved in Both Autophagy and Mitosis

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