Differential expression of p21-activated kinases (Paks) in ovarian cancer

Abstract

Objective: The high mortality rate of cancers is related to metastasis, which is a process involving alternation in cytoskeleton signaling pathways, increased directional cell migration and enhanced cell survival. Members of the Rho family of small GTPases (RhoA, Rac1 and Cdc42) have been found to be an important regulator for cytoskeleton reorganization. In mammalian cells, p21-activated serine/threonine kinases (Paks) were identified as effector molecules of Rac1 and Cdc42. To date, six members of Paks have been found and classified into two subgroups: Group 1, consisting of Paks1-3; and Group 2, consisting of Paks4-6. Paks can also be activated through GTPase-independent mechanisms, including direct phosphorylation by other kinases, such as protein kinase B. Due to their complicated activation processes and the presence of multiple downstream effectors, Paks play an important role in a wide range of cellular processes required for cancer progression. The objective of the present study is to characterize the expression levels and the signaling pathways of Paks in ovarian cancer in an attempt to explore the roles of Paks in ovarian carcinogenesis, with potential impacts on the development of targeted anticancer therapies. Methods: The differential expression of Pak1, phospho (p)-Pak2 Ser20 and Pak4 in ovarian cancer was assessed by immunohistochemistry in 60 clinical samples of ovarian tumours including cystadenomas, borderline tumours and carcinomas of different histological subtypes. By Western blot analysis, the expression of Pak1, p-Pak2 and Pak4 was also assessed in cell-lines of human ovarian epithelium (HOSE-6-3, HSOE 11-12, and HOSE-17-1) as compared with human ovarian carcinoma cell lines (SKOV-3, OVCAR-3). The effects of Paks on migration, invasion, proliferation and apoptosis in cell-lines of human ovarian epithelium and ovarian carcinoma as well as the upstream and downstream signaling pathway(s) of Paks in mediating their functions in ovarian cancer progession will also be determined. Results: Strong cytoplasmic staining of Pak1, p-Pak2 and Pak4 were observed in ovarian cancer cells. In contrast, there was weak or no expression of these proteins in borderline and benign ovarian tumours. There was no apparent difference between the expression of these proteins among the different histological subtypes when stratified into distinct diagnostic categories of benign, borderline and malignant. Furthermore, by Western blot analysis, Pak1, p-Pak2 and Pak4 were found to be expressed in ovarian carcinoma cell lines while their expression was absent in normal ovarian epithelium cell lines. Conclusion: Our findings suggest that Paks are likely to play a significant role in ovarian carcinogenesis and may be important regulators for the progression of ovarian cancer, with potential impacts on the development of targeted anticancer therapies.