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Oncotarget. 2016 Oct 4;7(40):65957-65967. doi: 10.18632/oncotarget.11781.

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

Author information

1
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
2
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
3
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080 S. Korea.
4
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722 S. Korea.
5
Stem Cell & Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351 S. Korea.
6
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06351 S. Korea.
7
Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.

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.

KEYWORDS:

NEK4; TRAIL; cancer; survivin

PMID:
27602754
PMCID:
PMC5323206
DOI:
10.18632/oncotarget.11781
[Indexed for MEDLINE]
Free PMC Article

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