Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid.
Redox balance influences differentiation status of neuroblastoma in the presence of all-trans retinoic acid.
复制标题
氧化还原平衡会影响神经细胞瘤的分化状态。
DOI：
10.1016/j.redox.2015.11.012
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发表时间：
2016-04
期刊：
影响因子：
11.4
通讯作者：
Kiningham KK
中科院分区：
文献类型：
--
作者：
Silvis AM;McCormick ML;Spitz DR;Kiningham KK
神经母细胞瘤是儿童时期最常见的颅外实体瘤；处于疾病 IV 期的患者肿瘤复发的可能性很高。类视黄醇疗法已被用作诱导肿瘤细胞分化和抑制复发的手段。在本研究中，用 10 μM 全反式视黄酸 (ATRA) 处理的人 SK-N-SH 神经母细胞瘤细胞中常见神经元分化标记物 [神经丝 M (NF-M)] 的表达随着细胞数量的减少而显着增加。这伴随着 MitoSOX 和 DCFH2 氧化的增加，这可能表明活性氧 (ROS)（例如 O2•− 和 H2O2）的稳态水平增加，这与 MnSOD 活性和免疫反应蛋白水平的增加相关。此外，在 96 小时，PEG-过氧化氢酶在 ATRA 处理的细胞（相对于对照）中更大程度地抑制 DCFH2 氧化信号，表明随着细胞变得更加分化，在过氧化物清除抗氧化剂（即谷胱甘肽、谷胱甘肽过氧化物酶和过氧化氢酶）不增加的情况下，H2O2 的稳态水平增加。此外，通过使用针对 MnSOD 的 siRNA 降低 SOD 活性，ATRA 诱导的 NF-M 在 48 小时和 72 小时的刺激得到增强。最后，在 MnSOD siRNA 或 PEG-过氧化氢酶存在下用 ATRA 处理 96 小时，可抑制 ATRA 诱导的 NF-M 表达增加。这些结果有力地支持了以下假设：O2−和 H2O2 稳态水平的变化显着促进 ATRA 诱导的神经母细胞瘤分化过程，并表明基于氧化还原的超氧化物代谢操作可能会增强视黄醇对神经母细胞瘤的治疗，从而改善患者的预后。 ROS 在神经母细胞瘤细胞的类维生素A分化中发挥作用。超氧化物和过氧化氢与 MnSOD 活性增加相协调。过氧化氢是促进分化的潜在信号分子。防止 H2O2 降解可能会改善基于类维生素A的神经母细胞瘤治疗。
Neuroblastoma is the most common extra-cranial solid tumor in childhood; and patients in stage IV of the disease have a high propensity for tumor recurrence. Retinoid therapy has been utilized as a means to induce differentiation of tumor cells and to inhibit relapse. In this study, the expression of a common neuronal differentiation marker [neurofilament M (NF-M)] in human SK-N-SH neuroblastoma cells treated with 10 μM all-trans retinoic acid (ATRA) showed significantly increased expression in accordance with reduced cell number. This was accompanied by an increase in MitoSOX and DCFH2 oxidation that could be indicative of increased steady-state levels of reactive oxygen species (ROS) such as O2•− and H2O2, which correlated with increased levels of MnSOD activity and immuno-reactive protein. Furthermore PEG-catalase inhibited the DCFH2 oxidation signal to a greater extent in the ATRA-treated cells (relative to controls) at 96 h indicating that as the cells became more differentiated, steady-state levels of H2O2 increased in the absence of increases in peroxide-scavenging antioxidants (i.e., glutathione, glutathione peroxidase, and catalase). In addition, ATRA-induced stimulation of NF-M at 48 and 72 h was enhanced by decreasing SOD activity using siRNA directed at MnSOD. Finally, treatment with ATRA for 96 h in the presence of MnSOD siRNA or PEG-catalase inhibited ATRA induced increases in NF-M expression. These results provide strong support for the hypothesis that changes in steady-state levels of O2•− and H2O2 significantly contribute to the process of ATRA-induced differentiation in neuroblastoma, and suggest that retinoid therapy for neuroblastoma could potentially be enhanced by redox-based manipulations of superoxide metabolism to improve patient outcome. A role for ROS is proposed for retinoid-differentiation of neuroblastoma cells. Superoxide and hydrogen peroxide coordinate with increased MnSOD activity. Hydrogen peroxide is a potential signaling molecule to promote differentiation. Preventing H2O2 degradation may improve retinoid based neuroblastoma therapies.