title: Serine palmitoyltransferase inhibitor myriocin induces growth inhibition of B16F10 melanoma cells through G(2) /M phase arrest.
abstract: OBJECTIVE
  Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti-cancer treatment have been sought from natural resources. Here, we have investigated anti-proliferative activity of myriocin, serine palmitoyltransferase inhibitor, in the de novo sphingolipid pathway, and its mechanism in B16F10 melanoma cells.
  
  
  METHODS
  We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate levels were analysed by HPLC.
  
  
  RESULTS
  Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G(2) /M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to myriocin, while expression of p53 and p21(waf1/cip1) was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate in myriocin-treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells.
  
  
  CONCLUSIONS
  Our results suggest that inhibition of sphingolipid synthesis by myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21(waf1/cip1) , followed by inhibition of cyclin B1 and cdc2, resulting in G(2) /M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by myriocin may be a potential target of mechanism-based therapy for this type of skin cancer.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Lee
authors.forename: K-M
authors.initials: KM
authors.lastname: Choi
authors.forename: M-H
authors.initials: MH
authors.lastname: Choi
authors.forename: S-Y
authors.initials: SY
authors.lastname: Ji
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: D-M
authors.initials: DM
authors.lastname: Sin
authors.forename: K-W
authors.initials: KW
authors.lastname: Oh
authors.forename: Y-M
authors.initials: YM
authors.lastname: Lee
authors.forename: J-T
authors.initials: JT
authors.lastname: Hong
authors.forename: Y-P
authors.initials: YP
authors.lastname: Yun
authors.forename: H-S
authors.initials: HS
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000235:genetics; D056744:Cyclin B1 / Q000096:biosynthesis / Q000235:genetics; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008246:Lysophospholipids / Q000096:biosynthesis / Q000235:genetics; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013109:Sphingomyelins / Q000096:biosynthesis / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D020687:cdc25 Phosphatases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C534700:Ccnb1 protein, mouse; D002518:Ceramides; D056744:Cyclin B1; D005229:Fatty Acids, Monounsaturated; D008246:Lysophospholipids; D013109:Sphingomyelins; D016159:Tumor Suppressor Protein p53; C060506:sphingosine 1-phosphate; D051102:Serine C-Palmitoyltransferase; D016203:CDC2 Protein Kinase; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases; D016283:Proto-Oncogene Proteins p21(ras); D013110:Sphingosine; C001996:thermozymocidin