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. 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.
Highlights
Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity, was originally identified as a depolarization-induced gene, KID-1, in the rat pheochromocytoma cell line PC12 [1]
The authenticity of all the cell lines was confirmed by determining DNA profiling of short tandem repeat (STR) whereas mycoplasma contamination was excluded with the help of Amelogenin (Beijing Microread Genetics Co., Ltd.) The antibodies used in this study are described in Supplementary Materials and Methods
We previously observed that a proto-oncogene with serine/threonine kinase activity, Pim-3, is aberrantly expressed in various malignant lesions, but not normal tissues of endoderm-derived organs such as the liver, pancreas, colon, and stomach [3,4,5, 6]
Summary
Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity, was originally identified as a depolarization-induced gene, KID-1, in the rat pheochromocytoma cell line PC12 [1]. Transcription was enhanced in EWS/ETS-induced malignant transformation of NIH3T3 cells [2], suggesting the involvement of Pim-3 in tumorigenesis. In line with these observations, we demonstrated that Pim-3 expression was enhanced in malignant lesions, but not normal tissues of endoderm-derived organs such as the liver [3], pancreas [4], colon [5], and stomach [6]. Baines and colleagues recently reported that Pim-3 suppression can sensitize pancreatic cancer cells to gemcitabine [11]. Pim-3 modulates Myc activity to promote tumorigenesis [13]
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