Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide.
Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide.
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DOI：
10.1002/ijc.26054
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发表时间：
2012-02-01
影响因子：
6.4
通讯作者：
Li, Guilan
中科院分区：
文献类型：
--
作者：
Jiang, Qing;Rao, Xiayu;Kim, Choon Young;Freiser, Helene;Zhang, Qingbo;Jiang, Ziying;Li, Guilan
尽管基于细胞的研究表明，γ-生育三烯醇（γTE）比其他形式的维生素E（包括γ-生育酚（γT））具有更强的抗癌活性，但γTE发挥作用的分子基础仍有待阐明。我们发现γ - te处理促进了人前列腺PC-3和LNCaP癌细胞的凋亡、坏死和自噬。为了寻找γ - te刺激效应的潜在机制，我们发现γ - te处理导致细胞内神经脂合成途径中的神经脂中间体二氢神经酰胺和二氢鞘氨醇显著增加，但对神经酰胺和鞘氨醇没有影响。这些鞘脂的升高在细胞死亡的生化和形态学迹象之前或同时发生，并且比γT诱导的更为明显，而γT诱导的细胞对γTE的摄取远高于γT。鞘脂积累在γ - te引起的死亡中的重要性被二氢鞘脂氨酸和二氢神经酰胺分别显著降低前列腺细胞系或LNCaP细胞的活力的观察所强调。此外，肉豆蔻蛋白，一种特殊的新生鞘脂合成抑制剂，抵消了γ - te诱导的细胞死亡。与这些基于细胞的研究一致，在裸鼠中，γTE抑制LNCaP异种移植物生长53% (P<0.05)，而γT抑制33% （P = 0.07）。这些发现提供了γ - te刺激癌细胞死亡的分子基础，并支持细胞内二氢神经酰胺和二氢鞘氨醇的升高可能是一种新的抗癌机制的观点。
Although cell-based studies have shown that γ-tocotrienol (γTE) exhibits stronger anticancer activities than other forms of vitamin E including γ-tocopherol (γT), the molecular bases underlying γTE-exerted effects remains to be elucidated. Here we showed that γTE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of γTE-provoked effects, we found that γTE 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 γTE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by γT, which accompanied with much higher cellular uptake of γTE than γT. The importance of sphingolipid accumulation in γTE-caused fatality was underscored by the observation that dihydrosphingosine and dihydroceramide potently reduced the viability of both prostate cell lines or LNCaP cells, respectively. In addition, myriosin, a specific inhibitor of de novo sphingolipid synthesis, counteracted γTE-induced cell death. In agreement with these cell-based studies, γTE inhibited LNCaP xenograft growth by 53% (P<0.05), compared with 33% (P = 0.07) by γT, in nude mice. These findings provide a molecular basis of γTE-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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影响因子：
2.9
作者：
Barve, Avantika;Khor, Tin Oo;Kong, Ah-Ng
通讯作者：
Kong, Ah-Ng
影响因子：
3.2
作者：
Ahn, EH;Schroeder, JJ
通讯作者：
Schroeder, JJ
影响因子：
2.9
作者：
Newmark, Harold L.;Huang, Mou-Tuan;Reddy, Bandaru S.
通讯作者：
Reddy, Bandaru S.
DOI：
10.1073/pnas.200357097
发表时间：
2000-10-10
影响因子：
11.1
作者：
Jiang, Q;Elson-Schwab, I;Ames, BN
通讯作者：
Ames, BN
影响因子：
4.8
作者：
Kraveka, Jacqueline M.;Li, Li;Bielawska, Alicja
通讯作者：
Bielawska, Alicja