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The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion

Oncogene volume 31, pages 4279–4289 (2012)Cite this article

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A Correction to this article was published on 29 March 2019

Abstract

Lysophosphatidic acid (LPA) is a biolipid that has diverse biological activities implicated in ovarian cancer initiation and progression. Previous studies have shown the critical role of the Rho/Rho-associated kinase (ROCK) pathway in LPA-induced ovarian cancer progression. However, detailed underlying mechanism by which the Rho/ROCK pathway induces ovarian cancer cell invasion is still incompletely understood. In the present study, we observed that the Rho/ROCK pathway is implicated in the production of proteolytic enzymes, leading to LPA-induced ovarian cancer cell invasion. LPA induced matrix metalloproteinase (MMP)-9 expression in CAOV-3 and PA-1 cells and urokinase-type plasminogen activator (uPA) expression in SKOV-3 cells. LPA-induced proteolytic enzyme expression was required for the invasion of ovarian cancer cells expressing corresponding enzymes. Pretreatment of cells with a pharmacological inhibitor of Rho/ROCK (Y-27632) or overexpression of a dominant-negative mutant of Rho (Rho N19) profoundly inhibited LPA-induced proteolytic enzyme expression as well as the invasive potential of ovarian cancer cells. In addition, transfection with dominant-negative Ras (Ras N17) significantly inhibited LPA-induced Rho activation as well as MMP-9 and uPA expression. Consistently, Y-27632 reduced LPA-induced nuclear factor (NF)-κB activation that is critical for proteolytic enzyme expression and cellular invasion. Collectively, we demonstrate a mechanism by which LPA promotes ovarian cancer progression through coordinate activation of a Ras/Rho/ROCK/NF-κB signaling pathway and the proteolytic enzyme secretion, providing novel biomarkers and promising therapeutic targets for ovarian cancer cell progression.

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Acknowledgements

Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2011-0025912 and 2011-0015761, HYL; 2011-0028284, JWH). We thank Professor Gordon B Mills for a plasmid-containing uPA promoter and invaluable discussion, Professor Aree Moon for Ras V12 and Ras N17 and Professor Taeg Kyu Kwon for MMP-9 promoters.

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Authors and Affiliations

  1. Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea

    K J Jeong, S Y Park, K H Cho, J Kang, C G Park & H Y Lee

  2. Department of Pathology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea

    J S Sohn

  3. Department of Microbiology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea

    J Lee

  4. Department of Pharmacology, College of Pharmacy, Sookmyung Women’s University, Seoul, Korea

    Y K Kim

  5. Department of Biochemistry and Molecular Biology, School of Pharmacy, Sungkyunkwan University, Suwon, Korea

    J W Han

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Jeong, K., Park, S., Cho, K. et al. The Rho/ROCK pathway for lysophosphatidic acid-induced proteolytic enzyme expression and ovarian cancer cell invasion. Oncogene 31, 4279–4289 (2012). https://doi.org/10.1038/onc.2011.595

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