Resistance to Cell Death Induction and its Overcome in Childhood Cancer Cells
| Project/Area Number |
17390301
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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 | Mie University |
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Principal Investigator |
KOMADA Yoshihiro Mie University, Department of Pediatric and Developmental Science, Professor (80186791)
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| Co-Investigator(Kenkyū-buntansha) |
AZUMA Eiichi Mie University Hospital, Cell Transplantation and Therapy Center, Associate Professor (50211008)
HORI Hiroki Mie University, Graduate Schoolof Medicine, Department of Pediatric and Developmental Science, Asscoiate Professor (40252366)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,240,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥840,000)
Fiscal Year 2007: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2005: ¥10,200,000 (Direct Cost: ¥10,200,000)
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| Keywords | Apoptosis / Caspase / Death receptor / Cell cycle / Signal transduction / PI3 Kinase / Akt pathway / MAP Kinase pathway / MAPキナーゼ / サイクリン蛋白 / 抗Fas抗体 / TRAIL |
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| Research Abstract |
The activation of caspase-3 and caspase-8 was found to be cell cycle-dependent. Cells expressing active form of caspase-3 were cyclin-A/B1, p27/kip-1 and Ki-67 negative but positive for cyclin E, whereas the expression of active form of caspase-8 was detected in cyclin-A/B1/E and Ki-67 negative cells. In addition, both activation of caspases and Fas-mediated apoptosis were completely abolished when leukemia cells were arrested at early G1 phase of the cell cycle. These results suggested that caspase-3 would be activated in cells entering late G1 or early S phase ; caspase-8 would be activated in middle or late G1 phase.
Phosphoinositide-3-kinase (P13-kinase) /Akt pathway was constitutively active in TRAIL(Tumor necrosis factor-related apoptosis-inducing ligand)-resistant leukemia cells, but not in sensitive cells. Phosphate and tensin homologue deleted on chromosome 10 (PTEN) level was the same in both sensitive and resistant cells, but resistant cells expressed more level of phosphorylated inactive form of PTEN than the sensitive cells. There was induction of apoptosis when resistant cells were treated with a combination of TRAIL and a PI3-kinase inhibitor. These results demonstrated that resistance to TRAIL-induced apoptosis could be induced through phosphorylation of Akt and PTEN.
Mitogen-activated kinase (MAPK) : JNK and p38 were constantly activated in leukemia cells, whereas ERK1/2 phosphorylation was found in 30% of B-lineage or T-lineage leukemia cells. When activation of ERK1/2 were inhibited, significant growth inhibition and cell death were induced. It is assumed that cross-talking among Death receptor-mediated signals, PI3-kinase/Akt pathway and MAPK pathway would be important for decision-making of cellular response to Death receptor stimulation
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] Cell cycle dependency of caspase activation in Fas-induced apoptosis in leukemia cells2007
Author(s)
Li, Y, Dida, F, Iwao, A, Deguchi, T, Azuma, E, Komada, Y
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Journal Title
Cancer Science 98(8)
Pages: 1174-1183
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Acquisition of Fas resistance by Fas receptor mutation in a childhood B-precursor acute lymphoblastic leukemia cell line, MML-12005
Author(s)
Inaba, H, Shimada, K, Zhou, YW, Ido, M, Buck, S, Yonehara, S, Kaplan, J, Komada, Y
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Journal Title
International Journal of Oncolology 27(2)
Pages: 573-579
Description
「研究成果報告書概要(欧文)」より
Related Report
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