By activating Fas/ceramide synthase 6/p38 kinase in lipid rafts, Stichoposide D inhibits growth of leukemia xenografts
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Seong-Hoon Yun1, Eun-Seon Park1, Sung-Won Shin1, Mi-Ha Ju2, Jin-Yeong Han3, Jin-Sook Jeong2, Sung-Hyun Kim4, Valentin A. Stonik5, Jong-Young Kwak1, Joo-In Park1
1Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea
2Department of Pathology, Dong-A University College of Medicine, Busan, South Korea
3Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, South Korea
4Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea
5G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far East Division, The Russian Academy of Sciences, Vladivostok, Russia
Joo-In Park, e-mail: [email protected]
Keywords: triterpene glycoside, lipid rafts, ceramide synthase 6, p38 kinase, apoptosis
Received: December 04, 2014 Accepted: July 17, 2015 Published: July 30, 2015
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 involved in its anti-leukemic activity. We also established that STD is able to enhance the chemosensitivity of K562 cells to etoposide or Ara-C. These data suggest that STD may be used alone or in combination with other chemotherapeutic agents to treat leukemia.
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