title: A novel regulatory mechanism of Pim-3 kinase stability and its involvement in pancreatic cancer progression.
abstract: Translationally controlled tumor protein (TCTP/TPT1) was identified from a yeast 2-hybrid screen and shown to interact with Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity. TCTP was aberrantly expressed in human pancreatic cancer cells and malignant ductal epithelial cells, but not in normal pancreatic duct epithelial cells adjacent to tumor foci of human pancreatic cancer tissue. Moreover, TCTP colocalized with Pim-3 both in human pancreatic cancer cells and in clinical tissues. Mapping studies revealed that the interaction between Pim-3 and TCTP occurred through the C-terminal region of Pim-3 and N-terminal region of TCTP. Although Pim-3 had no effect on TCTP expression or phosphorylation, overexpression of TCTP increased the amount of Pim-3 in a dose-dependent manner. Interestingly, RNAi-mediated ablation of TCTP expression reduced Pim-3 protein but not mRNA, through a mechanism involving the ubiquitin-proteasome degradation system. As a consequence of Pim-3 instability and subsequent degradation, tumor growth in vitro and in vivo was inhibited by arresting cell-cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens, and patients with highly expressed TCTP and Pim-3 presented with a more advanced tumor stage. These observations indicate that TCTP enhances Pim-3 stability to simultaneously promote and prevent cell-cycle progression and apoptosis, respectively. Hence, TCTP and Pim-3 serve a pivotal role in human pancreatic cancer with important ramifications for clinical diagnostic and therapeutic implications.
  
  
  CONCLUSIONS
  The present study provides a new idea and experimental evidence for recognizing TCTP/Pim-3 pathway as a target for therapy in human pancreatic cancer.
authors.affiliation: Room 1216, 2nd Building, Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 DongAn Road, Shanghai 200032, China. liyingyi@fudan.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Yu
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Ni
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Yang
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018450:Disease Progression; D004795:Enzyme Stability; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013379:Substrate Specificity; D000090324:Tumor Protein, Translationally-Controlled 1; D020798:Two-Hybrid System Techniques; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; C499249:PIM3 protein, human; C488192:Pim3 protein, mouse; D017346:Protein Serine-Threonine Kinases