ABSTRACT
Prostate tumor overexpressed-1 (PTOV1), a modulator of the Mediator transcriptional regulatory complex, is expressed at high levels in prostate cancer and other neoplasias in association with a more aggressive disease. Here we show that PTOV1 interacts directly with receptor of activated protein C kinase 1 (RACK1), a regulator of protein kinase C and Jun signaling and also a component of the 40S ribosome. Consistent with this interaction, PTOV1 was associated with ribosomes and its overexpression promoted global protein synthesis in prostate cancer cells and COS-7 fibroblasts in a mTORC1-dependent manner. Transfection of ectopic PTOV1 enhanced the expression of c-Jun protein without affecting the levels of c-Jun or RACK1 mRNA. Conversely, knockdown of PTOV1 caused significant declines in global protein synthesis and c-Jun protein levels. High levels of PTOV1 stimulated the motility and invasiveness of prostate cancer cells, which required c-Jun, whereas knockdown of PTOV1 strongly inhibited the tumorigenic and metastatic potentials of PC-3 prostate cancer cells. In human prostate cancer samples, the expression of high levels of PTOV1 in primary and metastatic tumors was significantly associated with increased nuclear localization of active c-Jun. These results unveil new functions of PTOV1 in the regulation of protein translation and in the progression of prostate cancer to an invasive and metastatic disease.
Subject(s)
Neoplasm Proteins/genetics , Protein Biosynthesis/genetics , Proto-Oncogene Proteins c-jun/genetics , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , COS Cells , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line , Cell Line, Tumor , Cell Movement/genetics , Chlorocebus aethiops , Disease Progression , Dogs , Humans , Madin Darby Canine Kidney Cells , Male , Mechanistic Target of Rapamycin Complex 1 , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Neoplasm Proteins/metabolism , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-jun/metabolism , Receptors for Activated C Kinase , Receptors, Cell Surface , Ribosomes/genetics , Ribosomes/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
INTRODUCTION: Currently, final diagnosis of prostate cancer (PCa) is based on histopathological analysis of needle biopsies, but this process often bears uncertainties due to small sample size, tumour focality and pathologist's subjective assessment. METHODS: Prostate cancer diagnostic signatures were generated by applying linear discriminant analysis to microarray and real-time RT-PCR (qRT-PCR) data from normal and tumoural prostate tissue samples. Additionally, after removal of biopsy tissues, material washed off from transrectal biopsy needles was used for molecular profiling and discriminant analysis. RESULTS: Linear discriminant analysis applied to microarray data for a set of 318 genes differentially expressed between non-tumoural and tumoural prostate samples produced 26 gene signatures, which classified the 84 samples used with 100% accuracy. To identify signatures potentially useful for the diagnosis of prostate biopsies, surplus material washed off from routine biopsy needles from 53 patients was used to generate qRT-PCR data for a subset of 11 genes. This analysis identified a six-gene signature that correctly assigned the biopsies as benign or tumoural in 92.6% of the cases, with 88.8% sensitivity and 96.1% specificity. CONCLUSION: Surplus material from prostate needle biopsies can be used for minimal-size gene signature analysis for sensitive and accurate discrimination between non-tumoural and tumoural prostates, without interference with current diagnostic procedures. This approach could be a useful adjunct to current procedures in PCa diagnosis.
