Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation

被引：17

作者：

Bhat, Vishwanath Kumble ^{[1
]}

Bernhart, Eva ^{[1
]}

Plastira, Ioanna ^{[1
]}

Fan, Kaiji ^{[2
,3
]}

Ghaffari-Tabrizi-Wizsy, Nassim ^{[4
]}

Wadsack, Christian ^{[5
]}

Rechberger, Gerald ^{[6
,7
]}

Eichmann, Thomas ^{[6
,7
]}

Asslaber, Martin ^{[8
]}

Spassova, Ivelina ^{[3
]}

Verhaegen, Monique E. ^{[9
]}

Malle, Ernst ^{[1
]}

Becker, Juergen C. ^{[3
,10
]}

Sattler, Wolfgang ^{[1
,7
]}

机构：

[1] Med Univ Graz, Div Mol Biol & Biochem, Gottfried Schatz Res Ctr, Neue Stiftingtalstr 6-6, A-8010 Graz, Austria

[2] Med Univ Graz, Dept Dermatol & Venereol, Graz, Austria

[3] Univ Hosp Essen, Dept Translat Skin Canc Res, Essen, Germany

[4] Med Univ Graz, Div Immunol & Pathophysiol, Otto Loewi Res Ctr, Graz, Austria

[5] Med Univ Graz, Dept Obstet & Gynecol, Graz, Austria

[6] Karl Franzens Univ Graz, Inst Mol Biosci, Graz, Austria

[7] BioTechMed Graz, Ctr Explorat Lipid, Graz, Austria

[8] Med Univ Graz, Inst Pathol, Diagnost & Res Ctr Mol Biomed, Graz, Austria

[9] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA

[10] German Canc Consortium DKTK DKFZ, Heidelberg, Germany

来源：

JOURNAL OF INVESTIGATIVE DERMATOLOGY | 2019年 / 139卷 / 04期

基金：

奥地利科学基金会;

关键词：

SPHINGOLIPID METABOLISM; GENE-EXPRESSION; CANCER; 1-PHOSPHATE; RECEPTOR; POLYOMAVIRUS; EPIDEMIOLOGY; ASSOCIATION; MECHANISMS; THERAPY;

D O I：

10.1016/j.jid.2018.10.024

中图分类号：

R75 [皮肤病学与性病学];

学科分类号：

100206 ;

摘要：

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.

引用

页码：807 / 817

页数：11

共 55 条

[31] The Sphingosine Kinase 1 Inhibitor 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)thiazole Induces Proteasomal Degradation of Sphingosine Kinase 1 in Mammalian Cells [J].