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[摘要]：Although cell-based studies have shown that c-tocotrienol (gamma TE) exhibits stronger anticancer activities than other forms of vitamin E including c-tocopherol (gamma T), the molecular bases underlying gamma TE-exerted effects remains to be elucidated. Here we showed that gamma TE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of gamma TE-provoked effects, we found that gamma TE treatment led to marked increase of intracellular dihydroceramide and dihydrosphingosine, the sphingolipid intermediates in de novo sphingolipid synthesis pathway but had no effects on ceramide or sphingosine. The elevation of these sphingolipids by gamma TE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by gamma T, which accompanied with much higher cellular uptake of gamma TE than gamma T. The importance of sphingolipid accumulation in gamma TE-caused fatality was underscored by the observation that dihydrosphingosine and dihydroceramide potently reduced the viability of both prostate cell lines and LNCaP cells, respectively. In addition, myriosin, a specific inhibitor of de novo sphingolipid synthesis, counteracted gamma TE-induced cell death. In agreement with these cell-based studies, gamma TE inhibited LNCaP xenograft growth by 53% (p < 0.05), compared to 33% (p = 0.07) by gamma T, in nude mice. These findings provide a molecular basis of gamma TE-stimulated cancer cell death and support the notion that elevation of intracellular dihydroceramide and dihydrosphingosine is likely a novel anticancer mechanism. |
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