Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid.
Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid.
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DOI：
10.1038/onc.2015.330
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发表时间：
2016-05
期刊：
影响因子：
8
通讯作者：
Yaegashi N
中科院分区：
文献类型：
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作者：
Kitatani K;Usui T;Sriraman SK;Toyoshima M;Ishibashi M;Shigeta S;Nagase S;Sakamoto M;Ogiso H;Okazaki T;Hannun YA;Torchilin VP;Yaegashi N
靶向细胞运动是播散和转移所必需的，具有治疗卵巢癌转移的潜力，并且需要揭示细胞运动的调节机制以开发新的治疗方法。侵袭性卵巢癌细胞自发形成突起，例如板状伪足，这是产生细胞运动动力所必需的。 siRNA 筛选鉴定出 II 类磷脂酰肌醇 3-激酶 C2β (PI3KC2β) 是参与卵巢癌细胞板状伪足形成的 PI3K 主要亚型。生物活性鞘脂神经酰胺已成为一种抗肿瘤脂质，用短链 C6-神经酰胺治疗可减少具有 PI3KC2β 驱动的板状伪足的卵巢癌细胞数量。药理学分析表明，长链神经酰胺通过抢救/回收途径从 C6-神经酰胺再生，至少部分介导了 C6-神经酰胺的作用。从机制上讲，神经酰胺与 PI3KC2β 的 PIK 催化结构域相互作用并影响其区室化，从而抑制 PI3KC2β 激活及其驱动的细胞运动。神经酰胺治疗还抑制上皮生长因子（一种促转移因子）促进的细胞运动。为了检查神经酰胺在卵巢癌转移中的作用，使用神经酰胺脂质体并证实其在体外抑制细胞运动。神经酰胺脂质体对人卵巢癌小鼠异种移植模型的腹膜转移具有抑制作用。 PI3KC2β 敲低细胞的转移对神经酰胺脂质体的治疗不敏感，这表明神经酰胺与 PI3KC2β 的相互作用在转移抑制中具有特定作用。我们的研究确定神经酰胺是一种生物活性脂质，可限制 PI3KC2β 控制的细胞运动，并且神经酰胺被提议用作卵巢癌的转移抑制脂质。这些发现可以转化为开发基于神经酰胺的转移性疾病疗法。
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. siRNA 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.