title: Cyclin-dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis.
abstract: OBJECTIVE
  As a cyclin-independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown.
  
  
  METHODS
  Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was measured by Western blotting, immunohistochemistry, and real-time 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 significantly 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.
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Longlong
authors.initials: L
authors.lastname: Cao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Jiechao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Junrong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Sijin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Xintao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Guangtan
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
authors.forename: Chaohui
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China. Cancer Research Center, Xiamen University, Xiamen, Fujian, China.
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China. Cancer Research Center, Xiamen University, Xiamen, Fujian, China. Sanford-Burnham Medical Research Institute, La Jolla, California. jiezhang@xmu.edu.cn hcmlr2002@163.com everbright99@gmail.com xuh@sanfordburnham.org.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning, China. jiezhang@xmu.edu.cn hcmlr2002@163.com everbright99@gmail.com xuh@sanfordburnham.org.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. jiezhang@xmu.edu.cn hcmlr2002@163.com everbright99@gmail.com xuh@sanfordburnham.org.
authors.forename: Changming
authors.initials: C
authors.lastname: Huang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian China. Cancer Research Center, Xiamen University, Xiamen, Fujian, China. jiezhang@xmu.edu.cn hcmlr2002@163.com everbright99@gmail.com xuh@sanfordburnham.org.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D051360:Cyclin-Dependent Kinase 5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011379:Prognosis; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000631:Aminopyridines; D051360:Cyclin-Dependent Kinase 5; D028884:Karyopherins; D008301:Maleimides; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C000604565:NS-0011; C495905:CDK5 protein, human