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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bhat, VK; Bernhart, E; Plastira, I; Fan, K; Ghaffari-Tabrizi-Wizsy, N; Wadsack, C; Rechberger, G; Eichmann, T; Asslaber, M; Spassova, I; Verhaegen, ME; Malle, E; Becker, JC; Sattler, W.
Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation.
J Invest Dermatol. 2019; 139(4):807-817
Doi: 10.1016/j.jid.2018.10.024
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PubMed
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- Führende Autor*innen der Med Uni Graz
- Bhat Kumble Vishwanath
- Sattler Wolfgang
- Co-Autor*innen der Med Uni Graz
- Asslaber Martin
- Becker Jürgen Christian
- Bernhart Eva Maria
- Eichmann Thomas
- Fan Kaiji
- Ghaffari Tabrizi-Wizsy Nassim
- Malle Ernst
- Plastira Ioanna
- Wadsack Christian
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- Abstract:
- 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 AKTS473 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Carcinoma, Merkel Cell - drug therapy, metabolism, pathology
- Cell Count - administration & dosage
- Cell Line, Tumor - administration & dosage
- Cell Proliferation - drug effects
- Fatty Acids, Monounsaturated - pharmacology
- Gene Expression Regulation, Neoplastic - drug effects
- Humans - administration & dosage
- Immunosuppressive Agents - pharmacology
- Merkel cell polyomavirus - immunology
- Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors, metabolism
- Polyomavirus Infections - drug therapy, metabolism, pathology
- RNA, Neoplasm - genetics
- Serine C-Palmitoyltransferase - antagonists & inhibitors, metabolism
- Skin Neoplasms - drug therapy, metabolism, pathology
- Tumor Virus Infections - drug therapy, metabolism, pathology