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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2303-2312
Number of pages10
JournalMolecular cancer therapeutics
Volume14
Issue number10
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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