title: Targeting sphingosine kinase-1 to inhibit melanoma.
abstract: Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hengst
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.forename: Todd E
authors.initials: TE
authors.lastname: Fox
authors.forename: Jong K
authors.initials: JK
authors.lastname: Yun
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D058990:Molecular Targeted Therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D019938:Cyclin D1; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D013110:Sphingosine; D019311:Staurosporine; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol; C530104:CCND1 protein, human; C060506:sphingosine 1-phosphate