Growth, Differentiation, Survival and Apoptosis in Human Neuroblastoma Cells

人神经母细胞瘤细胞的生长、分化、存活和凋亡

• 批准号: 14370250
• 负责人: SUGIMOTO Tohru
• 金额: $ 5.12万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370250/
• 关键词: Neuroblastoma; Growth; Differentiation; Apoptosis; Neurotrophic factor; Retinoid; Fenrefinide; ヒト神経芽腫; 生存

We have previously reported the signal transduction of TRK-A and TRK-B receptors by neurotrophic factors in human neuroblastoma cells (Jpn J Cancer Res 1994,Acta Pedliatr Jpn, Med Pediatr Oncol 2000 and Jpn J Cancer Res 2001). In this study the mechanisms of apoptosis by fenretinide was investigated.Fenretinide, which mediates apoptosis in neuroblastoma cells, is being considered as a novel therapeutic for neuroblastoma. However, the cytotoxic mechanisms of fenretinide have not been fully elucidated. Sustained-activation of JNK and p38 MAPK signaling has recently been shown to have a pivotal role in stress-induced apoptosis. Whether fenretinide activates the signaling in neuroblastoma cells is not known.In the present study, fenretinide induced sustained-activation of both JNK and p38 MAPK in neuroblastoma cells. Pretreatment with the antioxidant L-ascorbic acid almost completely inhibited the accumulation of fenretinide-induced intracellular reactive oxygen species (ROS), activation of JNK and p38 MAPK, and apoptosis. On the other hand, intracellular ROS production and activation of stress signaling was not altered by fenretinide in resistant neuroblastoma cells. Our study demonstrates that in neuroblastoma cells, fenretinide induces sustained-activation of JNK and p38 MAPK in an ROS-dependent manner, and indicates that JNK and p38 MAPK signaling might mediate fenretinide-induced apoptosis.Our results also indicate that suppression of the fenretinide-induced ROS productive system and the downstream JNK and p38 MAPK signaling pathways causes neuroblastoma cells to become resistant to fenretinide.

我们先前已经报道了TRK-A和TRK-B受体通过人神经母细胞瘤细胞中的神经营养因子的信号转导（Jpn J Cancer Res 1994，Acta Pedliatr Jpn，Med Pediatr Oncol 2000和Jpn J Cancer Res 2001）。本研究旨在探讨芬维A胺诱导神经母细胞瘤细胞凋亡的机制，芬维A胺可介导神经母细胞瘤细胞的凋亡，有望成为神经母细胞瘤的新型治疗药物。然而，芬维A胺的细胞毒性机制尚未完全阐明。JNK和p38 MAPK信号的持续激活最近被证明在应激诱导的细胞凋亡中具有关键作用。芬维A胺是否激活神经母细胞瘤细胞中的信号转导尚不清楚。在本研究中，芬维A胺诱导神经母细胞瘤细胞中JNK和p38 MAPK的持续激活。抗氧化剂L-抗坏血酸预处理几乎完全抑制了芬维A胺诱导的细胞内活性氧簇（ROS）的积累、JNK和p38 MAPK的激活以及细胞凋亡。另一方面，在耐药神经母细胞瘤细胞中，芬维A胺并没有改变细胞内ROS的产生和应激信号的激活。我们的研究结果表明，芬维A胺以ROS依赖的方式诱导神经母细胞瘤细胞持续激活JNK和p38 MAPK，JNK和p38 MAPK信号通路可能介导芬维A胺诱导的细胞凋亡，我们的研究结果还表明，芬维A胺诱导的ROS产生系统和下游JNK和p38 MAPK信号通路的抑制导致神经母细胞瘤细胞对芬维A胺产生耐药性。

项目成果

S.Osone, T.Sujimoto et al.: "Fenretinide induces sustained-activation of JNK/p38 and apoptosis in ROS-dependent manner in neuroblastome cells"Int J Cancer. (accepted). (2004)

S.Osone、T.Sujimoto 等人：“芬维A胺在神经母细胞中以 ROS 依赖性方式诱导 JNK/p38 持续激活和细胞凋亡”Int J Cancer。

Misawa A, Hosoi H, Tsuchida T, Sugimoto T.: "Rapamycin inhibits proliferation of human neuroblatoma cells without suppression on MycN"Int J Cancer. 20. 233-237 (2003)

Misawa A、Hosoi H、Tsuchida T、Sugimoto T.：“雷帕霉素抑制人神经母细胞瘤细胞的增殖而不抑制 MycN”Int J Cancer。

Y.Kuwahara, T.Sugimoto et al.: "Antitumer activity of Gefitinib in malignant rhabdoid tumor cells"Clin Cancer Res. (revised). (2004)

Y.Kuwahara、T.Sugimoto 等人：“吉非替尼在恶性横纹肌样肿瘤细胞中的抗肿瘤活性”Clin Cancer Res。

杉本 徹(分担): "神経芽腫、小児科学第2版"医学書院、東京. 1657 (2002)

Toru Sugimoto（撰稿人）：“神经母细胞瘤，儿科第 2 版”Igakushoin，东京 1657 年（2002 年）。

S.Osone, T.Sugimoto et al.: "Fenretinide induces sustained-activation of JNK/p38 and apoptosis in ROS-dependent manner in neuroblastome cells"Int J Cancer. (accepted). (2004)

S.Osone、T.Sugimoto 等人：“芬维A胺在神经母细胞中以 ROS 依赖性方式诱导 JNK/p38 持续激活和细胞凋亡”Int J Cancer。