Sunitinib Suppress Neuroblastoma Growth through Degradation of MYCN and Inhibition of Angiogenesis
Sunitinib Suppress Neuroblastoma Growth through Degradation of MYCN and Inhibition of Angiogenesis
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DOI：
10.1371/journal.pone.0095628
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发表时间：
2014-04-23
期刊：
影响因子：
3.7
通讯作者：
Serrano, Rosario
中科院分区：
文献类型：
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作者：
Calero, Raul;Morchon, Esther;Serrano, Rosario
神经母细胞瘤是一种发生在周围交感神经系统的肿瘤，是儿童时期最常见和最致命的颅外肿瘤。大多数高危神经母细胞瘤表现出MYCN原癌基因扩增和新血管生成增加。MYCN蛋白稳定化和血管生成均受通过受体酪氨酸激酶（RTK）的信号传导调节。因此，RTKs抑制剂有可能作为高危神经母细胞瘤的治疗选择。我们使用受体酪氨酸激酶抗体阵列来分析神经母细胞瘤中膜结合的RTK的活性，并发现多RTK抑制剂舒尼替尼来定制神经母细胞瘤细胞中RTK的活化。舒尼替尼通过诱导细胞凋亡和细胞周期阻滞抑制几种RTK，并对神经母细胞瘤细胞表现出强效抗肿瘤活性。舒尼替尼治疗通过抑制PI 3 K/AKT信号传导和GSK 3 β降低MYCN蛋白水平。这种效应与MYCN扩增的神经母细胞瘤细胞中VEGF分泌减少相关。舒尼替尼显著抑制裸鼠皮下MYCN扩增的神经母细胞瘤异种移植瘤的生长，并在体内表现出抗血管生成作用，减少肿瘤血管和降低MYCN表达。这些结果表明，舒尼替尼应作为高风险神经母细胞瘤患者的治疗选择进行测试。
Neuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most common and deadly extracranial tumor of childhood. The majority of high-risk neuroblastoma exhibit amplification of the MYCN proto-oncogene and increased neoangiogenesis. Both MYCN protein stabilization and angiogenesis are regulated by signaling through receptor tyrosine kinases (RTKs). Therefore, inhibitors of RTKs have a potential as a treatment option for high-risk neuroblastoma. We used receptor tyrosine kinase antibody arrays to profile the activity of membrane-bound RTKs in neuroblastoma and found the multi-RTK inhibitor sunitinib to tailor the activation of RTKs in neuroblastoma cells. Sunitinib inhibited several RTKs and demonstrated potent antitumor activity on neuroblastoma cells, through induction of apoptosis and cell cycle arrest. Treatment with sunitinib decreased MYCN protein levels by inhibition of PI3K/AKT signaling and GSK3 beta. This effect correlates with a decrease in VEGF secretion in neuroblastoma cells with MYCN amplification. Sunitinib significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude mice and demonstrated an anti-angiogenic effect in vivo with a reduction of tumor vasculature and a decrease of MYCN expression. These results suggest that sunitinib should be tested as a treatment option for high risk neuroblastoma patients.