Sphingosine kinase-1 protects multiple myeloma from apoptosis driven by cancer-specific inhibition of RTKs

Shuntaro Tsukamoto, Yuhui Huang, Motofumi Kumazoe, Connie Lesnick, Shuhei Yamada, Naoki Ueda, Takashi Suzuki, Shuya Yamashita, Yoon Hee Kim, Yoshinori Fujimura, Daisuke Miura, Neil E. Kay, Tait D. Shanafelt, Hirofumi Tachibana

研究成果: Contribution to journalArticle査読

25 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)2303-2312
ページ数10
ジャーナルMolecular cancer therapeutics
14
10
DOI
出版ステータス出版済み - 10 1 2015

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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