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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

Use of prolyl isomerase Pin1 as a molecular probe to identify cancer-specific phosphorylated proteins

Yokohama City University School of Medicine, Yokohama, Japan and Taiho Pharmaceutical, Co. Ltd., Saitama, Japan

Abstract

B8

The peptidyl-prolyl isomerase Pin1 regulates a subset of phosphorylated proteins by catalyzing the cis-trans isomerization of their specific phosphorylated Ser/Thr-Pro motifs. Pin1 is overexpressed in many types of human malignancies and may contribute to tumorigenesis by enhancing several oncogenic signaling pathways. Although Pin1 has been shown to be involved in cell transformation and in the maintenance of the malignant phenotype in prostate cancer, its specific substrates during these processes have not so far been determined. In our present study, we have utilized Pin1 as a molecular probe to capture cancer-specific phosphorylated proteins as diagnostic or prognostic markers. By the use of glutathione-S-transferase (GST) pull-downs and subsequent proteomic analyses using human prostate cancer and Dunning rat prostate cancer cells we have newly identified five prostate cancer-specific Pin1 binding proteins (PINBPs). We confirmed the up-regulation of these genes in prostate cancer cell lines and tissues, compared with non-cancerous cells and tissues. In addition, tissue micro-dissection based quantitative RT-PCR analysis of prostate cancer tissues further revealed that the expression of one of these Pin1-binding proteins (PINBP1) is closely associated with both a higher probability and a shorter period of tumor recurrence following surgery. These results indicate that Pin1-based proteomics analysis is a useful tool in the identification of cancer-specific phosphorylated proteins and that these factors are potential diagnostic and/or prognostic markers and anti-cancer targets.