Increased levels of DNA methyltransferases are associated with the tumorigenic capacity of prostate cancer cells
Increased levels of DNA methyltransferases are associated with the tumorigenic capacity of prostate cancer cells
复制标题
DOI：
10.3892/or.2012.2192
复制
发表时间：
2013-03-01
期刊：
影响因子：
4.2
通讯作者：
Festuccia, Claudio
中科院分区：
文献类型：
--
作者：
Gravina, Giovanni Luca;Ranieri, Guido;Festuccia, Claudio
DNA甲基化可能是前列腺癌最早的体细胞基因组变化，在肿瘤侵袭、生长和转移过程中发挥重要作用。近年来，一些DNA甲基转移酶（DNMTis）抑制剂已经在临床前模型和临床试验中被开发和评估。虽然这些化合物在治疗血液病方面是有效的，但在实体瘤和前列腺癌的临床试验中显示效果有限或没有效果。这可能是由于不适当的剂量方案导致毒性相关的不良事件。与其他抗靶点化合物一样，DNMTis在前列腺癌治疗中遇到的障碍之一可能是无法选择临床研究的患者，以及无法监测药物的疗效（如果不是研究结论的话）。从良性前列腺增生（BPH）和前列腺癌（PCa）患者的前列腺组织以及肿瘤和非肿瘤前列腺细胞系中提取原代培养物，检测DNMT的表达/活性，并监测阿扎胞苷的分子功效。我们观察到，在原代培养中，与BPH组织样本相比，来自PCa的培养物的DNMT活性水平以及DNMT1、DNMT3a和DNMT3b的蛋白水平更高，而在Gleason评分>= 7的PCa培养物中，与来自Gleason评分的培养物相比，DNMT1、DNMT3a和DNMT3b的蛋白水平明显更高
DNA methylation might be the earliest somatic genome changes in prostate cancer that also play an important role in the process of tumor invasion, growth and metastasis. In recent years, several inhibitors of DNA methyltransferases (DNMTis) have been developed and evaluated in pre-clinical models and in clinical trials. While these compounds are effective in the treatment of hematological conditions, clinical trials in solid tumors and in prostate cancer have shown limited or no efficacy. This may be attributed to inappropriate dose regimens leading to toxicity-related adverse events. As with other anti-target compounds, one of the obstacles encountered with DNMTis in prostate cancer could be the inability to select patients for the clinical studies as well as the inability to monitor the efficacy of the drug if not the conclusion of the study. Primary cultures derived from human prostatic tissues harvested from patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa) as well as neoplastic and non-neoplastic prostate cell lines were tested for DNMT expression/activity and to monitor azacitidine molecular efficacy. We observed that in primary cultures the levels of DNMT activity as well as the protein levels of DNMT1, DNMT3a and DNMT3b were higher in cultures derived from PCa compared to BPH tissue samples and significantly higher in cultures derived from PCa with Gleason scores >= 7 compared to those observed in cultures derived from Gleason scores