Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation
Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation
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DOI：
10.1016/j.jid.2018.10.024
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发表时间：
2019-04-01
影响因子：
6.5
通讯作者：
Sattler, Wolfgang
中科院分区：
文献类型：
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作者：
Bhat, Vishwanath Kumble;Bernhart, Eva;Sattler, Wolfgang
大多数默克尔细胞癌是一种高度侵袭性的皮肤神经内分泌癌，与默克尔细胞多瘤病毒感染有关。多瘤病毒的结合、内化和感染是由鞘糖脂介导的。除了受体功能，生物活性鞘脂被越来越多地认为是癌症几个特征的有效调节因素。默克尔细胞多瘤病毒刺细胞和默克尔细胞多瘤病毒e细胞表达丝氨酸棕榈酰转移酶亚基和鞘氨醇激酶(SK)1/2mRNA。诱导人肺成纤维细胞表达Merkel细胞多瘤病毒长肿瘤抗原可上调SPTLC1-3和SK1/2的表达。因此，我们利用药物抑制鞘磷脂代谢作为干扰Merkel细胞多瘤病毒刺默克尔细胞系增殖的一种选择。我们使用了myriocin(一种丝氨酸棕榈酰转移酶拮抗剂)和两种SK抑制剂(SKI-II和ABC294640)。在MKL-1和WAGA细胞中，Myriocin降低了细胞神经酰胺、鞘磷脂和1-磷酸鞘氨醇的含量。SKI-II增加了神经酰胺的种类，但降低了鞘磷脂和1-磷酸鞘氨醇的浓度。鞘磷脂稳态异常与细胞存活率降低、坏死增加、原天冬氨酸氨基转移酶-3和PARP加工、半胱氨酸氨基转移酶-3活性和AKT S473磷酸化降低有关。Myriocin和SKI-II可减少MKL-1和WAGA绒毛尿囊膜移植瘤的肿瘤体积和Ki-67染色。我们的数据表明，药物抑制鞘脂合成可能是默克尔细胞癌的一种潜在的治疗方法。
The majority of Merkel cell carcinoma, a highly aggressive neuroendocrine cancer of the skin, is associated with Merkel cell polyomavirus infection. Polyomavirus binding, internalization, and infection are mediated by glycosphingolipids. Besides receptor function, bioactive sphingolipids are increasingly recognized as potent regulators of several hallmarks of cancer. Merkel cell polyomavirus thorn and Merkel cell polyomavirus e cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomaviruselarge tumor antigen in human lung fibroblasts resulted in upregulation of SPTLC1-3 and SK 1/2 expression. Therefore, we exploited pharmacological inhibition of sphingolipid metabolism as an option to interfere with proliferation of Merkel cell polyomavirus thorn Merkel cell carcinoma cell lines. We used myriocin (a serine palmitoyl transferase antagonist) and two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells myriocin decreased cellular ceramide, sphingomyelin, and sphingosine-1-phosphate content. SKI-II increased ceramide species but decreased sphingomyelin and sphingosine-1-phosphate concentrations. Aberrant sphingolipid homeostasis was associated with reduced cell viability, increased necrosis, procaspase-3 and PARP processing, caspase-3 activity, and decreased AKT S473 phosphorylation. Myriocin and SKI-II decreased tumor size and Ki-67 staining of xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. Our data suggest that pharmacological inhibition of sphingolipid synthesis could represent a potential therapeutic approach in Merkel cell carcinoma.