title: By activating Fas/ceramide synthase 6/p38 kinase in lipid rafts, stichoposide D inhibits growth of leukemia xenografts.
abstract: Stichoposide D (STD) is a marine triterpene glycoside isolated from sea cucumbers. We examined the molecular mechanisms underlying the antitumor activity of STD in human leukemia cells. The role of Fas (CD95), ceramide synthase 6 (CerS6) and p38 kinase during STD-induced apoptosis was examined in human leukemia cells. In addition, the antitumor effects of STD in K562 and HL-60 leukemia xenograft models were investigated. We found that STD induces Fas translocation to lipid rafts, and thus mediates cell apoptosis. We also observed the activation of CerS6 and p38 kinase during STD-induced apoptosis. The use of methyl-β-cyclodextrin and nystatin to disrupt lipid rafts prevents the clustering of Fas and the activation of CerS6 and p38 kinase, and also inhibits STD-induced apoptosis. Specific inhibition by Fas, CerS6, and p38 kinase siRNA transfection partially blocked STD-induced apoptosis. In addition, STD has antitumor activity through the activation of CerS6 and p38 kinase without displaying any toxicity in HL-60 and K562 xenograft models. We observed that the anti-tumor effect of STD is partially prevented in CerS6 shRNA-silenced xenograft models. We first report that Fas/CerS6/p38 kinase activation in lipid rafts by STD is involved in its anti-leukemic activity. We also established that STD is able to enhance the chemosensitivity of K562 cells to etoposide or Ara-C. These data suggest that STD may be used alone or in combination with other chemotherapeutic agents to treat leukemia.
authors: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors: Seong-Hoon
authors: SH
authors: Yun
authors: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors: Eun-Seon
authors: ES
authors: Park
authors: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors: Sung-Won
authors: SW
authors: Shin
authors: Department of Pathology, Dong-A University College of Medicine, Busan, South Korea.
authors: Mi-Ha
authors: MH
authors: Ju
authors: Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, South Korea.
authors: Jin-Yeong
authors: JY
authors: Han
authors: Department of Pathology, Dong-A University College of Medicine, Busan, South Korea.
authors: Jin-Sook
authors: JS
authors: Jeong
authors: Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea.
authors: Sung-Hyun
authors: SH
authors: Kim
authors: G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, The Russian Academy of Sciences, Vladivostok, Russia.
authors: Valentin A
authors: VA
authors: Stonik
authors: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors: Jong-Young
authors: JY
authors: Kwak
authors: Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea.
authors: Joo-In
authors: JI
authors: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002470:Cell Survival; D002772:Cholera Toxin / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006027:Glycosides / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C491901:FAS protein, human; D006027:Glycosides; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D012503:Saponins; D014315:Triterpenes; D019014:fas Receptor; C000609767:stichoposide D; C001883:stichoposide; D002772:Cholera Toxin; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: apoptosis; ceramide synthase 6; lipid rafts; p38 kinase; triterpene glycoside