p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients.

  • Michelle K Y Siu, Hoi Yan Chan, +10 authors Annie N Y Cheung
  • Published 2010 in
    Proceedings of the National Academy of Sciences…

Abstract

Ovarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser(474), with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.

DOI: 10.1073/pnas.0907481107
0501001502011201220132014201520162017
Citations per Year

384 Citations

Semantic Scholar estimates that this publication has 384 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Siu2010p21activatedK4, title={p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients.}, author={Michelle K Y Siu and Hoi Yan Chan and Daniel S H Kong and Esther S Y Wong and Oscar G W Wong and Hextan Y S Ngan and Kar Fai Tam and Hongquan Zhang and Zhilun Li and Queeny K Y Chan and Sai Wah Tsao and Staffan Str{\"{o}mblad and Annie N Y Cheung}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2010}, volume={107 43}, pages={18622-7} }