2007 Fiscal Year Final Research Report Summary
Reseazrhof cell surface aminopeptidase function and translational in chemomcistance of gynecologic cancer
| Project/Area Number |
17591727
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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 |
Obstetrics and gynecology
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| Research Institution | Nagoya University |
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Principal Investigator |
SHIBATA Kiyosumi Nagoya University, University Hospital, Lecturer (90335026)
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| Co-Investigator(Kenkyū-buntansha) |
KIKKAWA Fumitaka Nagoya University, Graduate School of Medicine, Professor (40224985)
KAJIYAMA Hiroaki Nagoya University, University Hospital, Lecturer (00345886)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Gynecologic cancer / drug resistance / P-LAP / IRAP / APN / CD13 / bestatin / siRNA |
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| Research Abstract |
In this study, we investigated whether P-LAP/IRAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP/IRAP cDNA into endometrial adenocarcinoma cell line (A-MEC), andA-MEC-LAP cells displayed a 1.8-fold, 2.0-fold, and 1.7-fold increase in I050 against paclitaxel, carboplatin, and cisplatin respectively. While treatment of A-MEC-pc cells with carboplatin showed a much stronger PARP cleavage, comparable to the increase observed in cleaved caspases, A-MEC-LAP cells did not show any expression of cleaved PARR These results suggest that P-LAP/IRAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance. Furthermore, we examined whether the malignant potential of endometrial cancer enhanced by P-LAP/IRAP is due to increased glucose uptake via the P-LAP/IRAP-mediated activation of insulin signaling. A-MEC-LAP cells expressed a remarkably high level of GLUT4 proteins. 311-2-deoxyglucose uptake which responds to insulin in A-MEC-LAP cells was significantly higher than that of A-MEC-pc cells. P-LAP/IRAP was involved in the increasing malignant potential of endometrial cancer mediated by insulin. P-LAP/IRAP was suggested to be a potential new target of molecular-targeted therapy for endometrial cancer.
Next, we examined whether APN/CD13 alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. APN/CD13 inhibitor, bestatin inhibited the paclitaxel resistance in ovarian cancer cells. Bestatin and siRNAof APN/CD13 increased sensitivity to anticancer drugs (paclitaxel) via inhibition of mitochondria-mediated apoptosis. APN/CD13 was suggested to be a potential new target of molecular-targeted therapy for ovarian cancer.
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[Journal Article] Involvement of aminopeptidase N in enhanced chemosensitivity to paclitaxel in ovarian carcinoma in vitro and in vivo2007
Author(s)
Yamashita, M., Kajiyama, H., Terauchi, M., Shibata, K., Ino, K., Nawa, A., Mizutani, S., Kikkawa, F
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Journal Title
Int J Cancer 120
Pages: 2243-50
Description
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