Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells
Targeting Notch pathway induces growth inhibition and differentiation of neuroblastoma cells
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DOI：
10.1093/neuonc/noq101
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发表时间：
2010-12-01
期刊：
影响因子：
15.9
通讯作者：
Memo, Maurizio
中科院分区：
文献类型：
--
作者：
Ferrari-Toninelli, Giulia;Bonini, Sara Anna;Memo, Maurizio
高危神经母细胞瘤是一种严重的儿科肿瘤，其特征是预后差。了解肿瘤发生和发展的分子机制对于改善药物治疗具有战略意义。Notch最近被提出作为治疗多种癌症的药理学靶点，并正在成为一种新的神经母细胞瘤相关分子通路。然而，Notch在这种癌症中发挥的确切作用仍有待广泛研究。在这里，我们表明，Notch激活的锯齿状蛋白1配体增强神经母细胞瘤细胞的增殖，我们提出了可能使用的Notch阻断γ-分泌酶抑制剂（GSIs）在神经母细胞瘤治疗。在神经母细胞瘤细胞系上单独或与13-顺式视黄酸（RA）组合测试两种不同的GSI，化合物E和DAPT。分别选择SH-SY 5 Y和IMR-32细胞作为低恶性和高恶性的范例。单独使用，GSI诱导完全细胞生长停滞，促进神经元分化，并显着降低细胞运动。GSI和13-顺式RA的组合导致神经母细胞瘤细胞的生长抑制、分化和迁移增强。总之，我们的数据表明，GSI与13-顺式RA的组合提供了优于单一药物的治疗优势，表明神经母细胞瘤的潜在新疗法。
High-risk neuroblastoma is a severe pediatric tumor characterized by poor prognosis. Understanding the molecular mechanisms involved in tumor development and progression is strategic for the improvement of pharmacological therapies. Notch was recently proposed as a pharmacological target for the therapy of several cancers and is emerging as a new neuroblastoma-related molecular pathway. However, the precise role played by Notch in this cancer remains to be studied extensively. Here, we show that Notch activation by the Jagged1 ligand enhances the proliferation of neuroblastoma cells, and we propose the possible use of Notch-blocking gamma-secretase inhibitors (GSIs) in neuroblastoma therapy. Two different GSIs, Compound E and DAPT, were tested alone or in combination with 13-cis retinoic acid (RA) on neuroblastoma cell lines. SH-SY5Y and IMR-32 cells were chosen as paradigms of lower and higher malignancy, respectively. Used alone, GSIs induced complete cell growth arrest, promoted neuronal differentiation, and significantly reduced cell motility. The combination of GSIs and 13-cis RA resulted in the enhanced growth inhibition, differentiation, and migration of neuroblastoma cells. In summary, our data suggest that a combination of GSIs with 13-cis RA offers a therapeutic advantage over a single agent, indicating a potential novel therapy for neuroblastoma.