Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma.
Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma.
复制标题
DOI：
10.1158/0008-5472.can-08-2968
复制
发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Cleveland JL
中科院分区：
文献类型：
--
作者：
Rounbehler RJ;Li W;Hall MA;Yang C;Fallahi M;Cleveland JL
神经母细胞瘤是一种发生于神经嵴的儿科恶性肿瘤，具有MYCN扩增的高危神经母细胞瘤患者预后极差。酪氨酸羟化酶（TH）启动子驱动的TH-MYCN转基因小鼠模型忠实地再现了人MYCN扩增的神经母细胞瘤的许多特征。Myc癌蛋白在肿瘤发生中的关键下游靶标是鸟氨酸脱羧酶（Odc），其是多胺生物合成的限速酶。事实上，持续使用Odc自杀抑制剂α-二氟甲基鸟氨酸（DFMO）或Odc杂合性治疗，可显著损害Eμ-Myc转基因小鼠中的淋巴瘤发展，这些作用与诱导细胞周期蛋白依赖性激酶（Cdk）抑制剂p27 Kip 1有关，该抑制剂通常被Myc抑制。在这里，我们报告DFMO治疗，而不是Odc杂合性损害MYCN诱导的神经母细胞瘤，并在这种恶性肿瘤短暂的DFMO治疗是足以提供保护。DFMO对小鼠和人MYCN扩增的神经母细胞瘤的选择性抗癌作用也依赖于其使Myc的增殖反应失效的能力，然而在这种肿瘤背景下，DFMO靶向p21 Cip 1 Cdk抑制剂的表达，其也被Myc癌蛋白抑制。这些发现表明，靶向多胺通路的药物（如DFMO）可能在高危MYCN扩增的神经母细胞瘤中显示出疗效。
Neuroblastoma is a pediatric malignancy that arises from the neural crest and patients with high-risk neuroblastoma that typically harbor amplifications of MYCN have an extremely poor prognosis. The tyrosine hydroxylase (TH) promoter-driven TH-MYCN transgenic mouse model faithfully recapitulates many hallmarks of human MYCN-amplified neuroblastoma. A key downstream target of Myc oncoproteins in tumorigenesis is ornithine decarboxylase (Odc), the rate-limiting enzyme of polyamine biosynthesis. Indeed, sustained treatment with the Odc suicide inhibitor α-difluoromethylornithine (DFMO), or Odc heterozygosity, markedly impairs lymphoma development in Eμ-Myc transgenic mice, and these effects are linked to the induction of the cyclin dependent kinase (Cdk) inhibitor p27Kip1, which is normally repressed by Myc. Here we report that DFMO treatment, but not Odc heterozygosity impairs MYCN-induced neuroblastoma, and that in this malignancy transient DFMO treatment is sufficient to confer protection. The selective anti-cancer effects of DFMO on mouse and human MYCN-amplified neuroblastoma also rely on its ability to disable Myc's proliferative response, yet in this tumor context DFMO targets the expression of the p21Cip1 Cdk inhibitor, which is also suppressed by Myc oncoproteins. These findings suggest that agents such as DFMO that target the polyamine pathway may show efficacy in high-risk, MYCN-amplified neuroblastoma.