Agarwal Mukesh K, Agarwal Munna L, Athar Mohammad, Gupta Sanjay
Department of Medical Elementology and Toxicology, Hamdard University, New Delhi, India.
Cell Cycle. 2004 Feb;3(2):205-11. doi: 10.4161/cc.3.2.654.
Anti-cancer properties of palm oil have been attributed to the presence of tocotrienols and carotenoids. Studies from various laboratories have shown that tocotrienol-rich fraction (TRF) of palm oil inhibits cell growth and induces apoptosis in both preneoplastic and neoplastic cells. However, the mechanism by which TRF induces apoptosis remains largely unknown. Since several chemopreventive agents have been shown to utilize p53 pathway in negative regulation of cell growth, using human colon carcinoma RKO cells which express wild type p53, we investigated the effect of TRF on components of p53 signaling network. Treatment of cells with TRF resulted in a dose- and time- dependent inhibition of growth and colony formation. Further, TRF treatment of RKO cells resulted in the induction of WAF1/p21 which appears to be independent of cell cycle regulation and is transcriptionally upregulated in p53 dependent fashion. These results were further confirmed by using cells that express luciferase from a p53 responsive promoter where TRF treatment leads to activation of p53 reporter activity. TRF treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome c and induction of apoptotic protease-activating factor-1. This altered expression of Bcl2 family members triggered the activation of initiator caspase-9 followed by activation of effector caspase-3. These signaling cascades lead to condensed chromatin, DNA fragmentation and shrinkage of cell membrane resulting into apoptosis. Our data suggest that TRF-induced apoptosis in colon carcinoma cells is mediated by p53 signaling network which appears to be independent of cell cycle association.
棕榈油的抗癌特性归因于生育三烯酚和类胡萝卜素的存在。来自各个实验室的研究表明，棕榈油中富含生育三烯酚的部分（TRF）可抑制细胞生长，并诱导癌前细胞和肿瘤细胞凋亡。然而，TRF诱导凋亡的机制在很大程度上仍然未知。由于几种化学预防剂已被证明利用p53途径对细胞生长进行负调控，因此我们使用表达野生型p53的人结肠癌细胞RKO，研究了TRF对p53信号网络成分的影响。用TRF处理细胞导致生长和集落形成受到剂量和时间依赖性的抑制。此外，用TRF处理RKO细胞导致WAF1/p21的诱导，这似乎与细胞周期调控无关，并且以p53依赖的方式在转录水平上上调。通过使用来自p53反应性启动子表达荧光素酶的细胞进一步证实了这些结果，其中TRF处理导致p53报告基因活性的激活。TRF处理还导致Bax/Bcl2比值发生变化，有利于凋亡，这与细胞色素c的释放和凋亡蛋白酶激活因子-1的诱导有关。Bcl2家族成员的这种表达改变触发了起始半胱天冬酶-9的激活，随后是效应半胱天冬酶-3的激活。这些信号级联导致染色质浓缩、DNA片段化和细胞膜收缩，从而导致细胞凋亡。我们的数据表明，TRF诱导结肠癌细胞凋亡是由p53信号网络介导的，这似乎与细胞周期关联无关。
