Regulation of cell death by netrin-1 and its receptors and those alterations in human cancers
| Project/Area Number |
17390098
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East |
|---|
Principal Investigator |
ARAKAWA Hirofumi National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East, National Canser Center Research Institute, Cancer Medichin and Biophysics Division, Chief (70313088)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
|
|---|
| Keywords | Netrin-1 / p53 / apoptosis / axon guidance / tumor suppressor / cancer therapy / anti-apoptotic signaling / ネトリン / ネトリンレセプター / 細胞死 / 細胞死抑制 / カスペース |
|---|
| Research Abstract |
To clarify the role of netrin-1 in an anti-apoptotic signaling pathway, we added the purified recombinant netrin 1 to the culture medium of the cells infected with adenovirus p53 (Ad-p53). In the absence of netrin-1, infection with Ad-p53 strongly induced apoptosis in the infected cells. However, an addition of the recombinant netrin-1 protein at the various concentrations (from 200ng/ml to 1000ng/ml) strikingly blocked p53-indced apoptosis. Under the condition, all the target genes including p21/WAF1, p53R2, and MDM2, as well as p53 protein itself were highly expressed in the cells, implying netrin-1 does not affect p53 activation and its transcriptional activity. On the other hand, all the caspases examined including caspase-9, caspase-8 and caspase-3 were completely inhibited by netrin-1. Therefore we concluded that netrin-1 anti-apoptotic signaling is likely to block the down-stream molecules of p53-dependent apoptotic pathway. Interestingly, we have found that an unidentified receptor mediates netrin-1 anti-apoptotic signaling pathway.
These results suggest that the netrin-1 anti-apoptotic signaling pathway probably causes carcinogenesis, cancer metastasis and tolerance of cancer cells to anti-cancer drugs. Therefore, we think that further analysis of the mechanism for the netrin-1 signaling in anti-cell death pathway and its alterations in human cancers could provide a new strategy for cancer therapy in the future.
|
Report
(3 results)
Research Products
(15 results)
