title: Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells.
abstract: Resveratrol (RSV) is a plant-derived phytoalexin present in plants, whose pleiotropic effects for health benefits have been previously reported. Its anti-cancer activity is among the current topics for novel cancer treatment. Here, effects of RSV on cell proliferation and the sphingolipid metabolism of K562, a human leukemia cell line, were analyzed. Some experiments were also performed in HCT116, a human colon cancer cell line. RSV inhibited cell proliferation of both cell lines. Increased cellular ceramide and decreased sphingomyelin and S1P by RSV were observed in RSV-treated K562 cells. Further analysis revealed that acid sphingomyelinase mRNA and enzyme activity levels were increased by RSV. Desipramine, a functional ASMase inhibitor, prevented RSV-induced ceramide increase. RSV increased ATF3, EGR1, EGR3 proteins and phosphorylated c-Jun and FOXO3. However, co-transfection using these transcription factor expression vectors and ASMase promoter reporter vector revealed positive effects of EGR1 and EGR3 but not others. Electrophoresis mobility shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) assay demonstrated the direct binding of EGR1/3 transcription factors with ASMase 5'-promoter. These results indicate that increased EGR1/3 and ASMase expression play an important role in cellular ceramide increase by RSV treatment.
authors.affiliation: Department of Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine, Nagoya, Japan; College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mizutani
authors.affiliation: Department of Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Omori
authors.affiliation: College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kawamoto
authors.affiliation: College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sobue
authors.affiliation: College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ichihara
authors.affiliation: Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology and Molecular Biology, Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kyogashima
authors.affiliation: Department of Drug Information, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Tamiya-Koizumi
authors.affiliation: Tokai Gakuin University, Kakamigahara, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.affiliation: College of Life and Health Sciences, Chubu University, Kasugai, Japan. Electronic address: murate@isc.chubu.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murate
mesh_terms: D016588:Anticarcinogenic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077185:Resveratrol; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000008:administration & dosage*; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D016588:Anticarcinogenic Agents; D013267:Stilbenes; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase; D000077185:Resveratrol
keywords: Acid sphingomyelinase; Cell growth inhibition; Ceramide; ERG transcription factor; Resveratrol; Transcriptional regulation