Role of DNA methyltransferase 1 in hormone-resistant prostate cancer
Role of DNA methyltransferase 1 in hormone-resistant prostate cancer
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DOI：
10.1007/s00109-010-0640-3
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发表时间：
2010-09-01
影响因子：
4.7
通讯作者：
Wu, Chun-Te
中科院分区：
文献类型：
--
作者：
Chen, Miao-Fen;Chen, Wen-Cheng;Wu, Chun-Te
鉴于耐药（HR）前列腺癌患者的不良结局，需要新的策略来改善当前的治疗方案和/或开发新的治疗方法。因此，我们的目的是提供一个更好的了解参与HR的侵袭性肿瘤行为的分子机制，并开发更合理的抗肿瘤治疗。使用三种HR前列腺癌细胞系（雄激素受体（AR）阳性LNCaP-HR和22 RV 1-HR和AR阴性PC-3）。在体外和体内研究了肿瘤行为、治疗反应和HR相关信号传导的变化。结果表明，STAT 3的结构性激活和DNMT 1的过度表达在HR前列腺癌的转变中是重要的。此外，DNMT 1表达是维持STAT 3激活所必需的。当HR中的DNMT 1活性被阻断时，可以克服侵袭性肿瘤行为和治疗抗性，这在体外和体内实验中都可以看到。与抑制DNMT 1相关的潜在变化包括较少的上皮-间充质变化、较低的侵袭能力、较慢的肿瘤生长和受损的DNA修复能力，这与AR和p53状态无关。总之，与活化的STAT 3相关的DNMT 1表达改变可能在HR的转变中至关重要。靶向DNMT 1可能是治疗HR前列腺的有前途的策略，如抑制肿瘤生长和增强放射敏感性所证明的。这些发现为靶向治疗HR前列腺癌中的DNMT 1提供了证据。
Given the poor outcome of patients with hormone-resistant (HR) prostate cancer, new strategies are needed to improve the current therapeutic regimens and/or develop novel treatments. We therefore aimed to provide a better understanding of the molecular mechanisms involved in the aggressive tumor behavior of HR and develop more rational anti-tumor therapies. Three HR prostate cancer cell lines (androgen receptor (AR)-positive LNCaP-HR and 22RV1-HR and AR-negative PC-3) were used. Changes in tumor behavior, treatment response, and related signaling in HR were investigated in vitro and in vivo. The results revealed that constitutional activation of STAT3 and overexpressions of DNMT1 were important in the transition of HR prostate cancer. Furthermore, DNMT1 expression was required for the maintenance of STAT3 activation. When DNMT1 activity in HR was blocked, aggressive tumor behavior and treatment resistance could be overcome, which was seen in both in vitro and in vivo experiments. The underlying changes associated with inhibited DNMT1 included less epithelial-mesenchymal changes, less invasion ability, slower tumor growth, and impaired DNA repair ability, which are independent of AR and p53 status. In conclusion, altered DNMT1 expression associated with activated STAT3 may be crucial in the transition of HR. Targeting DNMT1 could be a promising strategy for the treatment of HR prostate, as evidenced by inhibited tumor growth and enhanced radiosensitivity. These findings provide evidence for therapeutically targeting DNMT1 in HR prostate cancer.