Sphingosine Kinase-1 Protects Multiple Myeloma from Apoptosis Driven by Cancer-Specific Inhibition of RTKs.
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.
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Shuntaro
S
Tsukamoto
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Yuhui
Y
Huang
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Motofumi
M
Kumazoe
Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Connie
C
Lesnick
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Shuhei
S
Yamada
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Naoki
N
Ueda
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Takashi
T
Suzuki
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Shuya
S
Yamashita
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan.
Yoon Hee
YH
Kim
Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
Yoshinori
Y
Fujimura
Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
Daisuke
D
Miura
Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Neil E
NE
Kay
Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Tait D
TD
Shanafelt
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.
Hirofumi
H
Tachibana
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
D000970:Antineoplastic Agents; D002392:Catechin; D064550:Death-Associated Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020794:Receptor Protein-Tyrosine Kinases; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; D000099157:Sphingosine Kinase; C045651:epigallocatechin gallate; C579096:DAPK1 protein, human; C112980:acid sphingomyelinase-1; C005682:safingol