title: Green tea polyphenol EGCG induces lipid-raft clustering and apoptotic cell death by activating protein kinase Cδ and acid sphingomyelinase through a 67 kDa laminin receptor in multiple myeloma cells.
abstract: EGCG [(-)-epigallocatechin-3-O-gallate], the major polyphenol of green tea, has cancer chemopreventive and chemotherapeutic activities. EGCG selectively inhibits cell growth and induces apoptosis in cancer cells without adversely affecting normal cells; however, the underlying molecular mechanism in vivo is unclear. In the present study, we show that EGCG-induced apoptotic activity is attributed to a lipid-raft clustering mediated through 67LR (67 kDa laminin receptor) that is significantly elevated in MM (multiple myeloma) cells relative to normal peripheral blood mononuclear cells, and that aSMase (acid sphingomyelinase) is critical for the lipid-raft clustering and the apoptotic cell death induced by EGCG. We also found that EGCG induces aSMase translocation to the plasma membrane and PKCδ (protein kinase Cδ) phosphorylation at Ser664, which was necessary for aSMase/ceramide signalling via 67LR. Additionally, orally administered EGCG activated PKCδ and aSMase in a murine MM xenograft model. These results elucidate a novel cell-death pathway triggered by EGCG for the specific killing of MM cells.
authors.affiliation: Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hirotsu
authors.forename: Motofumi
authors.initials: M
authors.lastname: Kumazoe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Goto
authors.forename: Kaori
authors.initials: K
authors.lastname: Sugihara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suda
authors.forename: Yukari
authors.initials: Y
authors.lastname: Tsurudome
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tachibana
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D017474:Receptors, Laminin / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013662:Tea / Q000737:chemistry
chemical_list: D017474:Receptors, Laminin; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D051745:Protein Kinase C-delta; D013108:Sphingomyelin Phosphodiesterase; D053148:Caspase 3