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首页> 外文期刊>American Journal of Cancer Research >Combining peptide TNIIIA2 with all-trans retinoic acid accelerates N-Myc protein degradation and neuronal differentiation in MYCN-amplified neuroblastoma cells
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Combining peptide TNIIIA2 with all-trans retinoic acid accelerates N-Myc protein degradation and neuronal differentiation in MYCN-amplified neuroblastoma cells

机译：肽TNIIIA2与全反式维甲酸结合可加速MYCN扩增的神经母细胞瘤细胞的N-Myc蛋白降解和神经元分化

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Neuroblastoma is one of the common solid tumors of childhood. Nearly half of neuroblastoma patients are classified into the high-risk group, and their 5-year event-free survival (EFS) rates remain unsatisfactory in the range of 30-40%. High-risk neuroblastoma is characterized by amplification of the MYCN gene and excessive expression of its protein product, N-Myc. Because N-Myc is a transcription factor for various pro-proliferative proteins, the excessive expression causes aberrant or blocked neuronal differentiation during development of sympathetic nervous system, which is a central aspect of neuroblastoma genesis. The current main treatment for high-risk neuroblastoma is intensive chemotherapy using anti-cancer drugs that induce apoptosis in tumor cells, but intensive chemotherapy has another serious risk of long-lasting side effects, so-called “late effects”, that occur many years after chemotherapy has ended. As a solution for such situation, differentiation therapy has been expected as a mild chemotherapy with a low risk of late effects, and an application of retinoic acid (RA) and its derivatives as treatment for high-risk neuroblastoma has long been attempted. However, the clinical outcome has not been sufficient with the use of retinoids, including all-trans retinoic acid (ATRA), mainly because of the inhibition of differentiation caused by N-Myc. In the present study, we succeeded in synergistically accelerating the ATRA-induced neuronal differentiation of MYCN-amplified neuroblastoma cells by combining a peptide derived from tenascin-C, termed TNIIIA2, which has a potent ability to activate β1-integrins. Accelerated differentiation was caused by a decrease in N-Myc protein level in neuroblastoma cells after the combined treatment of TNIIIA2 with ATRA. That is, combination treatment using ATRA with TNIIIA2 induced proteasomal degradation in the N-Myc oncoprotein of neuroblastoma cells with MYCN gene amplification, and this caused acceleration of neuronal differentiation and attenuation of malignant properties. Furthermore, an in vivo experiment using a xenograft mouse model showed a therapeutic potential of the combination administration of ATRA and TNIIIA2 for high-risk neuroblastoma. These results provide a new insight into differentiation therapy for high-risk neuroblastoma based on N-Myc protein degradation.
机译：神经母细胞瘤是儿童期常见的实体瘤之一。将近一半的神经母细胞瘤患者分类为高风险组，他们的5年无事件生存率（EFS）在30％至40％的范围内仍然不令人满意。高危神经母细胞瘤的特征在于MYCN基因的扩增和其蛋白质产物N-Myc的过度表达。因为N-Myc是各种促增殖蛋白的转录因子，所以过度表达会导致交感神经系统发育过程中异常或受阻的神经元分化，这是神经母细胞瘤发生的重要方面。目前，高危神经母细胞瘤的主要治疗方法是使用能诱导肿瘤细胞凋亡的抗癌药物进行强化化疗，但是强化化疗还有另一种严重的长期副作用的风险，即所谓的“后遗症”化疗结束后。作为针对这种情况的解决方案，已经期望分化疗法作为具有低晚期作用风险的温和化学疗法，并且长期以来尝试将视黄酸（RA）及其衍生物用于治疗高危神经母细胞瘤。但是，使用类视色素，包括全反式视黄酸（ATRA），临床结果还不够，主要是因为抑制了N-Myc引起的分化。在本研究中，我们成功地通过结合源自肌腱蛋白C的肽TNIIIA2来协同加速ATRA诱导的MYCN扩增的神经母细胞瘤细胞的神经元分化，该肽具有有效的激活β1-整合素的能力。 TNIIIA2与ATRA联合治疗后，神经母细胞瘤细胞中N-Myc蛋白水平降低导致分化加快。即，使用ATRA与TNIIIA2的组合治疗通过MYCN基因扩增诱导神经母细胞瘤细胞的N-Myc癌蛋白中的蛋白酶体降解，这导致神经元分化的加速和恶性特性的减弱。此外，使用异种移植小鼠模型的体内实验显示了ATRA和TNIIIA2联合给药对高危成神经细胞瘤的治疗潜力。这些结果为基于N-Myc蛋白降解的高危神经母细胞瘤的分化治疗提供了新的见识。

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