| A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells. | |
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MedLine Citation:
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PMID: 16187279 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In several recent studies, we have shown that P-LAP can be a poor prognostic factor and a factor of chemoresistance in endometrial carcinoma, especially in the advanced patients. In our study, we investigated whether P-LAP alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We transfected P-LAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells displayed a 1.8-fold, 2.0-fold and 1.7-fold increase in IC(50) against paclitaxel, carboplatin and cisplatin respectively. Translational downregulation by siRNA2 to P-LAP on A-MEC-LAP cells demonstrated 60%, 51% and 58% decrease in IC(50). To investigate the mechanism of P-LAP-induced chemoresistance, we also assessed whether P-LAP transfection had an effect on carboplatin-induced apoptotic death of A-MEC cells. A-MEC and A-MEC-pc (transfected with vector alone) cells exhibited a strong apoptotic response to carboplatin, while A-MEC-LAP cells exhibited a weak apoptotic response. In an attempt to identify the mechanism of the inhibitory effect on apoptotic response to carboplatin, we next assessed the expression of cleaved caspases and PARP cleavage. While treatment of A-MEC-pc cells with carboplatin exhibited increased levels of cleaved caspase 3, caspase 7 and caspase 9 compared to that after no treatment, A-MEC-LAP cells did not show any expression of these caspases. These results suggest that P-LAP reduces sensitivity to anticancer drugs via inhibition of mitochondria-mediated apoptosis, and may be a molecular target for conquering anticancer drug resistance. |
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Authors:
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Chihiro Kondo; Kiyosumi Shibata; Mikio Terauchi; Hiroaki Kajiyama; Kazuhiko Ino; Seiji Nomura; Akihiro Nawa; Shigehiko Mizutani; Fumitaka Kikkawa |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: International journal of cancer. Journal international du cancer Volume: 118 ISSN: 0020-7136 ISO Abbreviation: Int. J. Cancer Publication Date: 2006 Mar |
Date Detail:
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Created Date: 2006-01-24 Completed Date: 2007-05-29 Revised Date: 2009-11-24 |
Medline Journal Info:
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Nlm Unique ID: 0042124 Medline TA: Int J Cancer Country: United States |
Other Details:
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Languages: eng Pagination: 1390-4 Citation Subset: IM |
Affiliation:
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Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan. shiba@med.nagoya-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Apoptosis / drug effects* Blotting, Western Carboplatin / pharmacology* Caspases / metabolism Cell Line, Tumor Cystinyl Aminopeptidase / genetics, metabolism*, physiology Drug Resistance, Neoplasm* Endometrial Neoplasms / genetics, metabolism, pathology Enzyme Activation / drug effects Female Humans Paclitaxel / pharmacology Poly(ADP-ribose) Polymerases / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism RNA, Small Interfering / genetics Transfection bcl-X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/bcl-X Protein; 33069-62-4/Paclitaxel; 41575-94-4/Carboplatin; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.11.3/Cystinyl Aminopeptidase; EC 3.4.11.3/leucyl-cystinyl aminopeptidase; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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