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p21-Activated kinase 4 promotes prostate cancer progression through CREB

Oncogene volume 32, pages 2475–2482 (2013)Cite this article

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Abstract

Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.

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Acknowledgements

CRE-luciferase reporter gene containing 6x CRE binding sites was gift from Dr Jung EB at Chungbuk National University (Cheongju, Korea). This work was supported by a grant of the National Research Foundation of Korea (2012-0005747). MAS was supported by USPHS grant RO1 CA14397.

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Author notes

  1. M-H Park and H-S Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Medical Research Center, Chungbuk National University College of Medicine, Cheongju, Korea

    M-H Park, C-S Lee, S T You, D-J Kim, E-Y Shin & E-G Kim

  2. Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, Korea

    H-S Lee & B-H Park

  3. Department of Pathology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Korea

    M J Kang

  4. Department of Biological Sciences, KAIST, Daejeon, Korea

    W D Heo

  5. Departments of Medicine and Cell Biology, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA

    M A Schwartz

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Park, MH., Lee, HS., Lee, CS. et al. p21-Activated kinase 4 promotes prostate cancer progression through CREB. Oncogene 32, 2475–2482 (2013). https://doi.org/10.1038/onc.2012.255

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