Cyclin-dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis

Longlong Cao, Jiechao Zhou, Junrong Zhang, Sijin Wu, Xintao Yang, Xin Zhao, Huifang Li, Ming Luo, Qian Yu, Guangtan Lin, Huizhong Lin, Jianwei Xie, Ping Li, Xiaoqing Hu, Chaohui Zheng, Guojun Bu, Yun Wu Zhang, Huaxi Xu, Yongliang Yang, Changming HuangJie Zhang

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1419-1428
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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