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

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

doi:10.18632/oncotarget.11781

Abstract

The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) preferentially induces apoptosis in cancer cells. However, many tumors are resistant to TRAIL-induced apoptosis, and resistance mechanisms are not fully understood. To identify novel regulatory molecules of TRAIL resistance, we screened a siRNA library targeting the human kinome, and NEK4 (NIMA-related kinase-4) was identified. Knockdown of NEK4 sensitized TRAIL-resistant cancer cells and in vivo xenografts to cell death. In contrast, over expression of NEK4 suppressed TRAIL-induced cell death in TRAIL-sensitive cancer cells. In addition, loss of NEK4 resulted in decrease of the anti-apoptotic protein survivin, but an increase in apoptotic cell death. Interestingly, NEK4 was highly upregulated in tumor tissues derived from patients with lung cancer and colon cancer. These results suggest that inhibition of NEK4 sensitizes cancer cells to TRAIL-induced apoptosis by regulation of survivin expression.

Highlights

During the past decades, the strategy for cancer treatment has changed from relatively nonspecific cytotoxic chemical agents to selective molecular targetbased therapeutics [1]
To investigate whether lung cancer cells are resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced cell death, we examined the cytotoxic effect of TRAIL in lung cancer cells, including A549, H1299, H460, and SK-MES-1 cell lines
These results indicate that NIMA-related kinase-4 (NEK4) is only involved in regulating the TRAIL-mediated cell death pathway

Summary

Introduction

The strategy for cancer treatment has changed from relatively nonspecific cytotoxic chemical agents to selective molecular targetbased therapeutics [1]. Several mutations in apoptosis regulators, such as cellular FLICE-like inhibitory proteins are occasionally found in various types of tumor cells [17, 18]. These alterations are understandable because TRAIL is characterized as part of the immune system response to primary tumors, suggesting that primary tumors have already evaded TRAIL. To overcome the resistance to TRAIL that develops in cancer cells, numerous studies have suggested that combination therapy with specific targeting agents significantly enhances the toxicity of TRAIL in cancer cells [15]. The mechanism of overcoming TRAILresistance is not fully understood

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Results

Conclusion