2003 Fiscal Year Final Research Report Summary
Analysis of mechanisms for resistance against TRAIL induced apoptosis in gastrointestinal cancer and development of new strategy for cancer therapy using TRAIL
| Project/Area Number |
14570486
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
TAKIMOTO Rishu Sapporo Medical University, Instructor, 医学部, 助手 (10336399)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Junji Sapporo Medical University, Associate Professor, 医学部, 助教授 (20244345)
NIITSU Yoshiro Sapporo Medical University, Professor, 医学部, 教授 (10045502)
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| Project Period (FY) |
2002 – 2003
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| Keywords | TRAIL / cFLIP / DR5 |
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| Research Abstract |
AIM : TRAIL is a new member of death ligand which induces apoptosis in a number of cancers including gastrointestinal cancers. However, some cancers are refractory to TRAIL-induced apoptosis, and it is important to clarify the mechanisms of resistance against TRAIL. In this study, we used retrovirus library to examine the molecular mechanisms of TRAIL-induced apoptosis. METHODS and RESULTS ; We examined the sensitivity to TRAIL using a set of cancer cell lines. Two out of four showed sensitivity to TRAIL at low concentration, but others are resistant to TRAIL. We transduced retrovirus library into the sensitive cell line, SW480, and screened the clone to identify the molecule which inhibits TRAIL-mediated apoptosis. Two sets of screening revealed that cELIP is one of the molecules which can block TRAIL signaling. We found two other molecules can be the candidate, but still under examination. In order to augment the sensitivity to TRAIL, we knocked down cFLIP in SKOV3 cells using siRNA and succeeded to sensitize the cells to TRAIL. We then co-treated the cells with p53 modifying drug, CP31398, which induces DR5 expression, and found augmentation of TRAIL sensitivity. CONCLUSION : Down regulation of cFLIP by siRNA or up-regulation of DR5 will overcome the resistance against TRAIL and is expected to apply for clinical study.
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