Expression and function of the protein tyrosine phosphatases SHP-1 and SHP-2 in prostate cancer

Abstract: Prostate cancer is one of the most frequent cancers in males in Western countries. Radical prostatectomy serves as the first line of treatment for patients with localised prostate cancer. However, in many cases the cancer will recur. It is currently difficult to identify those patients at a high risk of tumour recurrence. Therefore, molecular markers associated with and predicting disease recurrence are needed to help identify patients and to better understand the signalling pathways in prostate cancer cells. The protein tyrosine kinase (PTK) receptors and cytosolic signalling proteins as well as the protein tyrosine phosphatases (PTPs) have important roles in the regulation of growth of the benign and malignant prostate gland. Here, we have studied the expression and function of the PTP SHP-1 in prostate cancer cell lines and in clinical material from patients that underwent radical prostatectomy. We have also analysed the expression of SHP-2 in prostate cancer cell lines and human prostate cancer tissue. We performed several different in vitro and in vivo experiments that were evaluated with methods such as immunohistochemical staining of tissue micro arrays (TMA), polymerase chain reaction (PCR), Western blot, eukaryotic cell transfections, proliferation assays, PTP enzymatic activity assay, caspase assay, flow cytometric assays, cell growth in vivo in nude mice, migration and invasion assays. Our results show that a low or absent SHP-1 expression might serve as a marker to identify prostate cancer patients at an increased risk of tumour recurrence. We also demonstrate that proliferation and apoptosis can be regulated by modulations of the SHP-1 expression in prostate cancer cells. SHP-1 expression and activity is reduced in the LNCaP cell line that was long-term stimulated with IL-6, showing that the cytokine might regulate SHP-1 activity. SHP-1 is also able to reduce growth of PC3 cells growing in vivo in nude mice. These results suggest that SHP-1 is a negative modulator by inhibiting prostate cancer cell proliferation through the growth factor and cytokine-induced pathways in prostate cancer cells. Our results also suggest that SHP-2 may have similar activity in prostate cancer.