2. Academic Validation
  3. Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs

  • Mol Cancer Ther. 2015 Oct;14(10):2303-12. doi: 10.1158/1535-7163.MCT-15-0185.
Shuntaro Tsukamoto 1,  Yuhui Huang 1,  Motofumi Kumazoe 1,  Connie Lesnick 2,  Shuhei Yamada 1,  Naoki Ueda 1,  Takashi Suzuki 1,  Shuya Yamashita 1,  Yoon Hee Kim 1,  Yoshinori Fujimura 3,  Daisuke Miura 3,  Neil E Kay 2,  Tait D Shanafelt 2,  Hirofumi Tachibana 4
Affiliations

Affiliations

  • 1 Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
  • 2 Department of Medicine, Mayo Clinic, Rochester, Minnesota.
  • 3 Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
  • 4 Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan. Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. Food Functional Design Research Center, Kyushu University, Fukuoka, Japan. tatibana@agr.kyushu-u.ac.jp.
PMID: 26264277 DOI: 10.1158/1535-7163.MCT-15-0185
Abstract

Activation of acid sphingomyelinase (ASM) leads to ceramide accumulation and induces apoptotic cell death in Cancer cells. In the present study, we demonstrate that the activation of ASM by targeting cancer-overexpressed 67-kDa laminin receptors (67LR) induces lipid raft disruption and inhibits receptor tyrosine kinase (RTK) activation in multiple myeloma cells. Sphingosine kinase 1 (SphK1), a negative regulator of ceramide accumulation with antiapoptotic effects, was markedly elevated in multiple myeloma cells. The silencing of SphK1 potentiated the apoptotic effects of the green tea polyphenol epigallocatechin-3-O-gallate (EGCG), an activator of ASM through 67LR. Furthermore, the SphK1 Inhibitor safingol synergistically sensitized EGCG-induced proapoptotic cell death and tumor suppression in multiple myeloma cells by promoting the prevention of RTK phosphorylation and activation of death-associated protein kinase 1 (DAPK1). We propose that targeting 67LR/ASM and SphK1 may represent a novel therapeutic strategy against multiple myeloma.

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Products
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  • HY-112384
    PKC 抑制剂
    PKC
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