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Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid

Oncogene volume 35, pages 2801–2812 (2016)Cite this article

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Abstract

Targeting cell motility, which is required for dissemination and metastasis, has therapeutic potential for ovarian cancer metastasis, and regulatory mechanisms of cell motility need to be uncovered for developing novel therapeutics. Invasive ovarian cancer cells spontaneously formed protrusions, such as lamellipodia, which are required for generating locomotive force in cell motility. Short interfering RNA screening identified class II phosphatidylinositol 3-kinase C2β (PI3KC2β) as the predominant isoform of PI3K involved in lamellipodia formation of ovarian cancer cells. The bioactive sphingolipid ceramide has emerged as an antitumorigenic lipid, and treatment with short-chain C6-ceramide decreased the number of ovarian cancer cells with PI3KC2β-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C6-ceramide through the salvage/recycling pathway, at least in part, mediated the action of C6-ceramide. Mechanistically, ceramide was revealed to interact with the PIK-catalytic domain of PI3KC2β and affect its compartmentalization, thereby suppressing PI3KC2β activation and its driven cell motility. Ceramide treatment also suppressed cell motility promoted by epithelial growth factor, which is a prometastatic factor. To examine the role of ceramide in ovarian cancer metastasis, ceramide liposomes were employed and confirmed to suppress cell motility in vitro. Ceramide liposomes had an inhibitory effect on peritoneal metastasis in a murine xenograft model of human ovarian cancer. Metastasis of PI3KC2β knocked-down cells was insensitive to treatment with ceramide liposomes, suggesting specific involvement of ceramide interaction with PI3KC2β in metastasis suppression. Our study identified ceramide as a bioactive lipid that limits PI3KC2β-governed cell motility, and ceramide is proposed to serve as a metastasis-suppressor lipid in ovarian cancer. These findings could be translated into developing ceramide-based therapy for metastatic diseases.

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Acknowledgements

This study was supported in part by JSPS KAKENHI Grants (40539235 to KK, 24390375 to NY and 23791801 to MT), a Health Labour Sciences Research Grant (201221019A to NY), and National Institutes of Health grants (U54 CA151881 to VPT and CA087584 to YAH). We also thank the laboratory members of the Departments of Microbiology and Immunology, and Obstetrics and Gynecology (Tohoku University, Sendai) for critical discussion.

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Authors and Affiliations

  1. Tohoku Medical Megabank Organization, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan

    K Kitatani, T Usui & N Yaegashi

  2. Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan

    K Kitatani, M Toyoshima, M Ishibashi, S Shigeta, M Sakamoto & N Yaegashi

  3. Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA

    S K Sriraman & V P Torchilin

  4. Department of Obstetrics and Gynecology, Yamagata University, Yamagata, Japan

    S Nagase

  5. Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan

    H Ogiso & T Okazaki

  6. Department of Medicine, Division of Hematology/Immunology, Kanazawa Medical University, Ishikawa, Japan

    T Okazaki

  7. Stony Brook Cancer Center and Department of Medicine, Stony Brook University, Stony Brook, NY, USA

    Y A Hannun

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Kitatani, K., Usui, T., Sriraman, S. et al. Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35, 2801–2812 (2016). https://doi.org/10.1038/onc.2015.330

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