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.
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Research Article|
March 27 2012
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
Shuntaro Tsukamoto;
Shuntaro Tsukamoto
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Keisuke Hirotsu;
Keisuke Hirotsu
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Motofumi Kumazoe;
Motofumi Kumazoe
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Yoko Goto;
Yoko Goto
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Kaori Sugihara;
Kaori Sugihara
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Takafumi Suda;
Takafumi Suda
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Yukari Tsurudome;
Yukari Tsurudome
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Takashi Suzuki;
Takashi Suzuki
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Shuya Yamashita;
Shuya Yamashita
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Yoonhee Kim;
Yoonhee Kim
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Yuhui Huang;
Yuhui Huang
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Koji Yamada;
Koji Yamada
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
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Hirofumi Tachibana
Hirofumi Tachibana
1
*Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan
†Laboratory of Functional Food Design, Department of Functional Metabolic Design, Bio-Architecture Center, Kyushu University, Fukuoka 812-8581, Japan
1To whom correspondence should be addressed (email tatibana@agr.kyushu-u.ac.jp).
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Publisher: Portland Press Ltd
Received:
October 17 2011
Revision Received:
January 11 2012
Accepted:
January 19 2012
Accepted Manuscript online:
January 19 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (2): 525–534.
Article history
Received:
October 17 2011
Revision Received:
January 11 2012
Accepted:
January 19 2012
Accepted Manuscript online:
January 19 2012
Citation
Shuntaro Tsukamoto, Keisuke Hirotsu, Motofumi Kumazoe, Yoko Goto, Kaori Sugihara, Takafumi Suda, Yukari Tsurudome, Takashi Suzuki, Shuya Yamashita, Yoonhee Kim, Yuhui Huang, Koji Yamada, Hirofumi Tachibana; 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. Biochem J 15 April 2012; 443 (2): 525–534. doi: https://doi.org/10.1042/BJ20111837
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