Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death
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So Jung Park1, Doo Sin Jo1, Se-Young Jo2, Dong Woon Shin1, Sangmi Shim3, Yoon Kyung Jo1, Ji Hyun Shin1, Ye Jin Ha2, Seong-Yun Jeong2, Jung Jin Hwang2, Young Sam Kim4, Young-Ah Suh2, Jong Wook Chang5,6, Jin Cheon Kim2,7, Dong-Hyung Cho1
1Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea
2Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea
3Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080 S. Korea
4Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722 S. Korea
5Stem Cell & Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351 S. Korea
6Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06351 S. Korea
7Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea
Jin Cheon Kim, email: firstname.lastname@example.org
Dong-Hyung Cho, email: email@example.com
Keywords: NEK4, survivin, cancer, TRAIL
Received: February 19, 2016 Accepted: August 09, 2016 Published: September 01, 2016
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.
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