Dysregulated PAK4 and chemosensitivity in ovarian cancer: an in vitro study

Ovarian cancer is regarded as the most lethal gynecological malignancy around the world. Despite the advancing medical improvements in both surgery and chemotherapy, the mortality rate did not appear to be reduced. This could be account for the late diagnosis of ovarian cancer until advanced stage. Recently, p-21 activated kinase 4 (PAK4), as a potential significant prognostic marker of ovarian cancer, has been widely studied on its contribution in oncogenesis properties. It was suggested that PAK4 proteins were activated and confer chemoresistance in ovarian cancers. In this study, we hypothesized that the up-regulation of PAK4 in ovarian cancers maybe resulted from mutations and amplification in genomic DNA level. Investigations on PAK4 genetic alterations were carried out. Recurrent mutations were found in the kinase domain of PAK4 in three ovarian cancer cell lines and two clinical samples. Single mutation was found in the exon 3 of PAK4 coding for GTPase binding domain (GTB). Amplifications of PAK4 genomic DNA were also found in four ovarian cancer cell lines. On top of that, dysregulated PAK4 level in chemosensitivity ovarian cancer cell line, A2780s showed PAK4 contribution in protection against apoptosis. Meanwhile PAK4 transfected chemoresistance cell line A2780cp also showed similar effect to PAK4 transfected A2780s. Kinase-dead and constitutively active PAK4 did not show any significance contribution to the apoptosis property. This may suggest that PAK4 do not operate all kinase domains towards apoptotic function. Immortalized normal ovarian epithelial cell line, HOSE6-3 was also upregulated with PAK4 transfection. However it did not induce the oncogenesis property of cell survival.published_or_final_versionPathologyMasterMaster of Medical Science