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.
Highlights
Multiple myeloma is the second most common hematologic malignancy
Activated acid sphingomyelinase (ASM) induces lipid raft disruption We used an ASM assay to identify a dose-dependent increase in ASM activity following treatment of multiple myeloma U266 cells with low concentrations of EGCG (Fig. 1A)
Displacement of cholesterol from the lipid raft on the plasma membrane occurs after generation of ceramide by ASM [17], and EGCG has been shown to induce disruption of cholesterol-rich lipid rafts in colon cancer cells [27]
Summary
Multiple myeloma is the second most common hematologic malignancy. It is an incurable disease with an average survival of 5 years following high-dose chemotherapy and autologous stem cell transplantation or treatment with novel drugs such as lenalidomide and bortezomib [1]. Pathologic studies suggest that increased 67LR expression is correlated with lesions histologic severity and tumor progression [4]. The overexpression of 67LR can induce adhesion-mediated drug resistance and chemotherapy resistance [7]. These findings support a vital role for 67LR in cancer progression
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