2003 Fiscal Year Final Research Report Summary
Growth, Differentiation, Survival and Apoptosis in Human Neuroblastoma Cells
| Project/Area Number |
14370250
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
SUGIMOTO Tohru Kyoto Prefectural University of Medicine, Professor, 医学研究科, 教授 (90117888)
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| Co-Investigator(Kenkyū-buntansha) |
HOSOI Hajime Kyoto Prefectural University of Medicine, Assistant Professor, 医学研究科, 講師 (20238744)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Neuroblastoma / Growth / Differentiation / Apoptosis / Neurotrophic factor / Retinoid / Fenrefinide |
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| Research Abstract |
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.
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