Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated ApoptosisThrough multiple mechanisms
Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated ApoptosisThrough multiple mechanisms
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DOI：
10.1002/pros.20653
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发表时间：
2007-11-01
期刊：
影响因子：
2.8
通讯作者：
Watson, R. William G.
中科院分区：
文献类型：
--
作者：
Gill, Catherine;Walsh, Sinead E.;Watson, R. William G.
背景。前列腺癌发生和发展的一个关键因素是凋亡调节蛋白的表达改变，这使得细胞对激素和化疗都有耐药性。据报道，白藜芦醇是一种具有化学预防特性的膳食成分，可使多种类型的癌细胞对凋亡再敏感。本研究旨在探讨白藜芦醇预处理对激素难治性前列腺癌细胞（PC-3和DU145）致敏性凋亡的影响及其机制。用几个既定的参数评估细胞凋亡，用Western blot和流式细胞术分析蛋白表达。通过RNAi实现IAP的敲除，而通过pi3激酶抑制剂ly294002预孵育实现Akt磷酸化的抑制。白藜芦醇预处理使PC-3和DU145细胞对特异性靶向死亡受体（TRAIL、Fas、TNF α）的药物敏感，但对通过其他机制启动细胞凋亡的药物（依托泊苷、紫杉醇、Tunicamycin、Thapsigargin）不敏感。白藜芦醇预处理改变PC-3细胞中IAPs和Bax的表达，降低Akt磷酸化，导致caspase活化和凋亡增加。虽然siRNA敲除IAPs不能模拟白藜芦醇的作用，但LY294002抑制Akt磷酸化可使PC-3细胞对TRAIL诱导的凋亡增敏，而对etopo苷或tunicamycin则没有增敏作用。改变晚期雄激素非依赖型疾病的细胞凋亡易感性需要操纵广泛的信号通路。使用白藜芦醇或抑制Akt磷酸化可能是治疗前列腺癌的一种重要治疗方法，可与传统治疗方法结合使用。
BACKGROUND. A critical factor in prostate cancer development and progression is the altered expression of apoptotic regulatory proteins which renders cells resistant to both hormone- and chemo-therapies. Resveratrol, a dietary component with chemopreventive properties has been reported to resensitize a variety of cancer cell types to apoptosis. In the current study, the ability of resveratrol pre-treatment to sensitize hormone refractory prostate cancer cell lines (PC-3 and DU145) to apoptosis and the mechanisms involved were investigated.METHODS. Apoptosis was assessed using several established parameters and protein expression was analyzed by Western blot and flow cytometry. IAP knockdown was achieved using RNAi while inhibition of Akt phosphorylation was achieved by pre-incubation with the PI3-kinase inhibitor LY294002.RESULTS. Pre-treatment with resveratrol sensitized PC-3 and DU145 cells to agents that specifically target death receptors (TRAIL, Fas, TNF alpha) but not agents that initiate apoptosis through other mechanisms (Etoposide, Paclitaxel, Tunicamycin, Thapsigargin). Resveratrol pretreatment altered the expression of IAPs and Bax, and decreased Akt phosphorylation in PC-3 cells, leading to increased caspase activation and apoptosis. While knockdown of IAPs using siRNA did not mimic the effects of resveratrol, inhibition of Akt phosphorylation using LY294002 sensitized PC-3 cells to TRAIL induced apoptosis but not to etoposide or tunicamycin.CONCLUSION. Altering apoptotic susceptibility in advanced androgen independent disease requires manipulation of a broad signaling pathway. Use of resveratrol or inhibition of Akt phosphorylation may represent an important therapeutic approach in combination with conventional therapies for the treatment of prostate cancer.