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

Abstract

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.