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Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells

Oncogene volume 35, pages 2178–2185 (2016)Cite this article

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Abstract

p21-activated kinases (Paks) are Cdc42/Rac-activated serine–threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1-amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13-amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21Cip and decreased expression of cyclin B1. These findings suggest that small-molecule inhibitors of Pak1 may have a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification.

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Acknowledgements

We thank M. Einarson (Fox Chase Cancer Center, High Throughput and Translational Core Facility) for assistance with cell cycle analysis and the Cell Culture Facility. We thank D. Connolly (FCCC), N. Tonks (CSHL) and G. Mills (MD Anderson) for ovarian cancer cell lines and for insightful comments on the manuscript. This work was supported by grants from the National Institutes of Health to JC (R01-CA142928 and R01-CA148805), Ovarian SPORE P50 CA083638 (Pilot Award to JC), Fox Chase Cancer Center (P30-CA006927), as well as by an appropriation from the State of Pennsylvania.

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Authors and Affiliations

  1. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    T Y Prudnikova, O Villamar-Cruz, S J Rawat & J Chernoff

  2. Deparment of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA

    K Q Cai

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  1. T Y Prudnikova
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Correspondence to J Chernoff.

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Prudnikova, T., Villamar-Cruz, O., Rawat, S. et al. Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene 35, 2178–2185 (2016). https://doi.org/10.1038/onc.2015.278

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