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

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 10 Pg. 2303-12 (Oct 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 26264277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Catechin
• epigallocatechin gallate
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Receptor Protein-Tyrosine Kinases
• DAPK1 protein, human
• Death-Associated Protein Kinases
• acid sphingomyelinase-1
• Sphingomyelin Phosphodiesterase
• Sphingosine
• safingol

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Catechin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Death-Associated Protein Kinases (metabolism)
• Drug Synergism
• Enzyme Activation
• Female
• Humans
• Membrane Microdomains (metabolism)
• Mice, Inbred BALB C
• Multiple Myeloma (drug therapy, enzymology)
• Phosphotransferases (Alcohol Group Acceptor) (physiology)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Signal Transduction
• Sphingomyelin Phosphodiesterase (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays