Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2
Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2
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DOI：
10.1530/erc-13-0077
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发表时间：
2013-10-01
影响因子：
3.9
通讯作者：
Holly, J. M. P.
中科院分区：
文献类型：
--
作者：
Biernacka, K. M.;Uzoh, C. C.;Holly, J. M. P.
在西方社会，临床相关的前列腺癌（PCa）更为常见，越来越多的男性患有与西方生活方式相关的合并症，主要是糖尿病，其特征是高胰岛素血症和高血糖症。胰岛素样生长因子及其结合蛋白（IGFBPs）是营养对生长影响的重要介质，在前列腺癌的发生发展中起着关键作用。我们使用DU 145、PC3和LNCaP PCa细胞系来研究高脂血症如何改变它们对多西他赛的反应。使用台盼蓝染料排斥测定来确定细胞死亡的百分比。使用蛋白质免疫印迹法测定蛋白质丰度。使用ELISA测量IGFBP2的水平。利用siRNA技术实现IGFBP2基因沉默。DNA甲基化使用组合二硫键限制性分析进行评估。染色质免疫沉淀法检测IGFBP2基因相关组蛋白H3和H4的乙酰化状态。高脂血症使紫杉醇诱导的DU145细胞凋亡减少40%，LNCaP细胞凋亡减少88%。这种减少的细胞死亡是由葡萄糖诱导的IGFBP2上调介导的，因为沉默IGFBP2否定了高糖的存活效应。葡萄糖通过增加与IGFBP2基因启动子相关的组蛋白的乙酰化来增加IGFBP2。这一发现可能对治疗策略具有重要意义，因为表观遗传调节可能是可逆的。
Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.