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 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.
Highlights
Ceramide is a structural component of the membrane with important roles in the regulation of cell growth, cell differentiation, apoptosis, and cell senescence [1]
We found that treatment with Stichoposide D (STD) increases the expression of ceramide synthase 6 (CerS6) in K562 and HL-60 cells (Fig. 1C, 1D)
To investigate whether extracellular signal regulating kinase (ERK), Jun N-terminal kinase (JNK), and p38 kinase were involved in STD-induced apoptosis, K562 and HL-60 cells were treated with STD for a range of times, and mitogen-activated protein kinases (MAPKs) protein levels were measured by Western blot analysis
Summary
Ceramide is a structural component of the membrane with important roles in the regulation of cell growth, cell differentiation, apoptosis, and cell senescence [1]. Obeid et al [4] reported that in leukemia, the synthetic ceramide analog. C2-ceramide is capable of inducing DNA fragmentation. Resistance to radiation therapy developed because of defective ceramide metabolism has been reported in Burkitt’s lymphoma and myeloid leukemia [5]. Manipulation of ceramide metabolism in patients to promote ceramide production may be helpful in chemotherapeutic treatment [1]. There is demand for a novel compound that is able to augment the production of ceramide during chemotherapy, potentiating cell killing and leading to more effective anti-leukemic strategies
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