Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Cancer Res. 2010 Apr 15;70(8):3239-48. doi: 10.1158/0008-5472.CAN-09-3186. Epub 2010 Apr 13.
To identify potential mechanisms underlying prostate cancer chemotherapy response and resistance, we compared the gene expression profiles in high-risk human prostate cancer specimens before and after neoadjuvant chemotherapy and radical prostatectomy. Among the molecular signatures associated with chemotherapy, transcripts encoding inhibitor of DNA binding 1 (ID1) were significantly upregulated. The patient biochemical relapse status was monitored in a long-term follow-up. Patients with ID1 upregulation were found to be associated with longer relapse-free survival than patients without ID1 increase. This in vivo clinical association was mechanistically investigated. The chemotherapy-induced ID1 upregulation was recapitulated in the prostate cancer cell line LNCaP. Docetaxel dose-dependently induced ID1 transcription, which was mediated by ID1 promoter E-box chromatin modification and c-Myc binding. Stable ID1 overexpression in LNCaP increased cell proliferation, promoted G(1) cell cycle progression, and enhanced docetaxel-induced cytotoxicity. These changes were accompanied by a decrease in cellular mitochondria content, an increase in BCL2 phosphorylation at serine 70, caspase-3 activation, and poly(ADP-ribose) polymerase cleavage. In contrast, ID1 siRNA in the LNCaP and C42B cell lines reduced cell proliferation and decreased docetaxel-induced cytotoxicity by inhibiting cell death. ID1-mediated chemosensitivity enhancement was in part due to ID1 suppression of p21. Overexpression of p21 in LNCaP-ID1-overexpressing cells restored the p21 level and reversed ID1-enhanced chemosensitivity. These molecular data provide a mechanistic rationale for the observed in vivo clinical association between ID1 upregulation and relapse-free survival. Taken together, it shows that ID1 expression has a novel therapeutic role in prostate cancer chemotherapy and prognosis.
为了确定前列腺癌化疗反应和耐药的潜在机制，我们比较了新辅助化疗和根治性前列腺切除术前高危人前列腺癌标本的基因表达谱。在与化疗相关的分子特征中，编码 DNA 结合抑制因子 1（ID1）的转录本显著上调。在长期随访中监测患者的生化复发情况。结果发现，ID1 上调的患者无病生存率长于 ID1 无增加的患者。对这种体内临床相关性进行了机制研究。在前列腺癌细胞系 LNCaP 中重现了化疗诱导的 ID1 上调。多西他赛呈剂量依赖性诱导 ID1 转录，这是通过 ID1 启动子 E 盒染色质修饰和 c-Myc 结合介导的。在 LNCaP 中稳定过表达 ID1 可增加细胞增殖，促进 G1 细胞周期进程，并增强多西他赛诱导的细胞毒性。这些变化伴随着细胞线粒体含量减少、BCL2 丝氨酸 70 位磷酸化增加、半胱天冬酶-3 激活和多聚（ADP-核糖）聚合酶切割。相反，LNCaP 和 C42B 细胞系中的 ID1 siRNA 通过抑制细胞死亡减少细胞增殖并降低多西他赛诱导的细胞毒性。ID1 介导的化疗敏感性增强部分归因于 ID1 对 p21 的抑制。在 LNCaP-ID1 过表达细胞中过表达 p21 可恢复 p21 水平并逆转 ID1 增强的化疗敏感性。这些分子数据为观察到的 ID1 上调与无复发生存之间的体内临床相关性提供了机制依据。综上所述，这些结果表明 ID1 表达在前列腺癌化疗和预后中有新的治疗作用。
