Although cell-based studies have shown that gamma-tocotrienol (gammaTE) exhibits stronger anticancer activities than other forms of vitamin E including gamma-tocopherol (gammaT), the molecular bases underlying gammaTE-exerted effects remains to be elucidated. Here we showed that gammaTE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of gammaTE-provoked effects, we found that gammaTE 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 gammaTE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by gammaT, which accompanied with much higher cellular uptake of gammaTE than gammaT. The importance of sphingolipid accumulation in gammaTE-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 gammaTE-induced cell death. In agreement with these cell-based studies, gammaTE inhibited LNCaP xenograft growth by 53% (p < 0.05), compared to 33% (p = 0.07) by gammaT, in nude mice. These findings provide a molecular basis of gammaTE-stimulated cancer cell death and support the notion that elevation of intracellular dihydroceramide and dihydrosphingosine is likely a novel anticancer mechanism.
