By activating Fas/ceramide synthase 6/p38 kinase in lipid rafts, stichoposide D inhibits growth of leukemia xenografts

Oncotarget
Seong-Hoon YunJoo-In Park

Abstract

Stichoposide D (STD) is a marine triterpene glycoside isolated from sea cucumbers. We examined the molecular mechanisms underlying the antitumor activity of STD in human leukemia cells. The role of Fas (CD95), ceramide synthase 6 (CerS6) and p38 kinase during STD-induced apoptosis was examined in human leukemia cells. In addition, the antitumor effects of STD in K562 and HL-60 leukemia xenograft models were investigated. We found that STD induces Fas translocation to lipid rafts, and thus mediates cell apoptosis. We also observed the activation of CerS6 and p38 kinase during STD-induced apoptosis. The use of methyl-β-cyclodextrin and nystatin to disrupt lipid rafts prevents the clustering of Fas and the activation of CerS6 and p38 kinase, and also inhibits STD-induced apoptosis. Specific inhibition by Fas, CerS6, and p38 kinase siRNA transfection partially blocked STD-induced apoptosis. In addition, STD has antitumor activity through the activation of CerS6 and p38 kinase without displaying any toxicity in HL-60 and K562 xenograft models. We observed that the anti-tumor effect of STD is partially prevented in CerS6 shRNA-silenced xenograft models. We first report that Fas/CerS6/p38 kinase activation in lipid rafts by STD is inv...Continue Reading

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Citations

Sep 19, 2017·Investigational New Drugs·Teresa Liliana Wargasetia, Widodo
Jan 15, 2020·Current Medicinal Chemistry·Dario MatuljaDean Marković
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Nov 10, 2021·Critical Reviews in Food Science and Nutrition·Yifan ZhouBaojun Xu

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Methods Mentioned

BETA
transfection
flow cytometry
xenograft
xenografts
density-gradient centrifugation
confocal microscopy

Software Mentioned

SPSS
CalcuSyn
AllStars

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