Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation
Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation
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DOI：
10.1158/1535-7163.mct-06-0014
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Agarwal, Chapla
中科院分区：
文献类型：
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作者：
Kaur, Manjinder;Agarwal, Rajesh;Agarwal, Chapla
前列腺癌是西方世界老年男性确诊的第二大癌症。流行病学研究表明，改变饮食可能是减少包括前列腺癌在内的各种癌症的有效方法，因此，近年来饮食营养素的癌症预防效果受到越来越多的关注。我们最近发现葡萄籽提取物(GSE)在培养和异种移植中抑制晚期人前列腺癌DU145细胞的生长并诱导其凋亡死亡。由于前列腺癌最初是一种雄激素依赖的恶性肿瘤，在这里，我们使用LNCaP人前列腺癌细胞作为模型来评估GSE的疗效和相关机制。GSE处理细胞会导致细胞在12小时内脱离，就像在失巢失巢细胞中所发生的那样，并导致活细胞显著减少，主要是由于它们的凋亡死亡。GSE诱导的细胞失巢和凋亡伴随着粘着斑激酶水平的显著降低，而caspase-3、caspase-9和聚(ADP-核糖)聚合酶裂解增加；然而，GSE引起caspase依赖和caspase非依赖的细胞凋亡，细胞色素c和凋亡诱导因子释放到胞浆中。更多的研究表明，GSE导致DNA损伤诱导共济失调毛细血管扩张突变激酶和Chk2的激活，以及P53 Ser15的磷酸化和移位到线粒体，这可能是诱导细胞凋亡的另一种机制。N-乙酰半胱氨酸可减轻GSE诱导的细胞凋亡、细胞生长抑制和细胞死亡，并参与活性氧的产生。总之，这些结果显示了GSE对LNCaP细胞的影响，并建议在前列腺癌动物模型中进行更多的体内疗效研究。
Prostate cancer is the second leading cancer diagnosed in elderly males in the Western world. Epidemiologic studies suggest that dietary modifications could be an effective approach in reducing various cancers, including prostate cancer, and accordingly cancer-preventive efficacy of dietary nutrients has gained increased attention in recent years. We have recently shown that grape seed extract (GSE) inhibits growth and induces apoptotic death of advanced human prostate cancer DU145 cells in culture and xenograft. Because prostate cancer is initially an androgen-dependent malignancy, here we used LNCaP human prostate cancer cells as a model to assess GSE efficacy and associated mechanisms. GSE treatment of cells led to their detachment within 12 hours, as occurs in anoikis, and caused a significant decrease in live cells mostly due to their apoptotic death. GSE-induced anoikis and apoptosis were accompanied by a strong decrease in focal adhesion kinase levels, but an increase in caspase-3, caspase-9, and poly(ADP-ribose) polymerase cleavage; however, GSE caused both caspase-dependent and caspase-independent apoptosis as evidenced by cytochrome c and apoptosis-inducing factor release into cytosol. Additional studies revealed that GSE causes DNA damage-induced activation of ataxia telangiectasia mutated kinase and Chk2, as well as p53 Ser15 phosphorylation and its translocation to mitochondria, suggesting this to be an additional mechanism for apoptosis induction. GSE-induced apoptosis, cell growth inhibition, and cell death were attenuated by pretreatment with N-acetylcysteine and involved reactive oxygen species generation. Together, these results show GSE effects in LNCaP cells and suggest additional in vivo efficacy studies in prostate cancer animal models.