TY - JOUR
T1 - Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer
T2 - Potential of ceramide as a metastasis-suppressor lipid
AU - Kitatani, K.
AU - Usui, T.
AU - Sriraman, S. K.
AU - Toyoshima, M.
AU - Ishibashi, M.
AU - Shigeta, S.
AU - Nagase, S.
AU - Sakamoto, M.
AU - Ogiso, H.
AU - Okazaki, T.
AU - Hannun, Y. A.
AU - Torchilin, V. P.
AU - Yaegashi, N.
N1 - Funding Information:
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.
Publisher Copyright:
© 2016 Macmillan Publishers Limited.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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 C 6 -ceramide decreased the number of ovarian cancer cells with PI3KC2β-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C 6 -ceramide through the salvage/recycling pathway, at least in part, mediated the action of C 6 -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.
AB - 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 C 6 -ceramide decreased the number of ovarian cancer cells with PI3KC2β-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C 6 -ceramide through the salvage/recycling pathway, at least in part, mediated the action of C 6 -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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U2 - 10.1038/onc.2015.330
DO - 10.1038/onc.2015.330
M3 - Article
C2 - 26364609
AN - SCOPUS:84941710478
VL - 35
SP - 2801
EP - 2812
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 21
ER -
