Inhibition of never in mitosis A (NIMA)-related kinase-4 reduces survivin expression and sensitizes cancer cells to TRAIL-induced cell death.
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.
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
So Jung
SJ
Park
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
Doo Sin
DS
Jo
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Se-Young
SY
Jo
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
Dong Woon
DW
Shin
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080 S. Korea.
Sangmi
S
Shim
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
Yoon Kyung
YK
Jo
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
Ji Hyun
JH
Shin
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Ye Jin
YJ
Ha
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Seong-Yun
SY
Jeong
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Jung Jin
JJ
Hwang
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722 S. Korea.
Young Sam
YS
Kim
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Young-Ah
YA
Suh
Stem Cell & Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351 S. Korea.|Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 06351 S. Korea.
Jong Wook
JW
Chang
Asan Institute for Medical Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.|Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505 S. Korea.
Jin Cheon
JC
Kim
Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi-do, 17104 S. Korea.
Dong-Hyung
DH
Cho
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000072379:NIMA-Related Kinases / Q000378:metabolism*; D011379:Prognosis; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D000072379:NIMA-Related Kinases; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C107489:BIRC5 protein, human; C505653:TNFSF10 protein, human; C547589:NEK4 protein, human
NEK4; TRAIL; cancer; survivin