Gottfried Schatz Research Center, Division of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria; Department of Translational Skin Cancer Research, University Hospital Essen, Essen, Germany.
J Invest Dermatol. 2019 Apr;139(4):807-817. doi: 10.1016/j.jid.2018.10.024. Epub 2018 Nov 3.
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 and Merkel cell polyomavirus cells express serine palmitoyl transferase subunits and sphingosine kinase (SK) 1/2 mRNA. Induced expression of Merkel cell polyomavirus-large 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 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 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.
大多数 Merkel 细胞癌是一种高度侵袭性的皮肤神经内分泌癌，与 Merkel 细胞多瘤病毒感染有关。多瘤病毒结合、内化和感染是由糖脂介导的。除了受体功能外，生物活性神经酰胺也越来越被认为是几种癌症特征的有效调节剂。Merkel 细胞多瘤病毒和 Merkel 细胞多瘤病毒细胞表达丝氨酸棕榈酰转移酶亚基和鞘氨醇激酶（SK）1/2 mRNA。在人肺成纤维细胞中诱导表达 Merkel 细胞多瘤病毒大肿瘤抗原导致 SPTLC1-3 和 SK 1/2 表达上调。因此，我们利用鞘脂代谢的药理学抑制作为干扰 Merkel 细胞多瘤病毒 Merkel 细胞癌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、神经鞘氨醇和鞘氨醇-1-磷酸的含量。SKI-II 增加了神经酰胺的种类，但降低了神经鞘氨醇和鞘氨醇-1-磷酸的浓度。异常的神经酰胺稳态与细胞活力降低、坏死增加、procaspase-3 和 PARP 加工、caspase-3 活性降低以及 AKT 磷酸化减少有关。myriocin 和 SKI-II 降低了异种移植 MKL-1 和 WaGa 肿瘤在绒毛尿囊膜上的肿瘤大小和 Ki-67 染色。我们的数据表明，鞘脂合成的药理学抑制可能是 Merkel 细胞癌的一种潜在治疗方法。
