TY - JOUR
T1 - Cyclin-dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis
AU - Cao, Longlong
AU - Zhou, Jiechao
AU - Zhang, Junrong
AU - Wu, Sijin
AU - Yang, Xintao
AU - Zhao, Xin
AU - Li, Huifang
AU - Luo, Ming
AU - Yu, Qian
AU - Lin, Guangtan
AU - Lin, Huizhong
AU - Xie, Jianwei
AU - Li, Ping
AU - Hu, Xiaoqing
AU - Zheng, Chaohui
AU - Bu, Guojun
AU - Zhang, Yun Wu
AU - Xu, Huaxi
AU - Yang, Yongliang
AU - Huang, Changming
AU - Zhang, Jie
N1 - Publisher Copyright:
©2015 AACR.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown. Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and realtime PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth. Results: CDK5 level was signi fi cantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis. Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.
AB - Purpose: As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown. Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and realtime PCR. The subcellular translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth. Results: CDK5 level was signi fi cantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis. Conclusions: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells.
UR - http://www.scopus.com/inward/record.url?scp=84927638065&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-1950
DO - 10.1158/1078-0432.CCR-14-1950
M3 - Article
C2 - 25609066
AN - SCOPUS:84927638065
SN - 1078-0432
VL - 21
SP - 1419
EP - 1428
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -