Document Detail


A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells.
MedLine Citation:
PMID:  16187279     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Chihiro Kondo; Kiyosumi Shibata; Mikio Terauchi; Hiroaki Kajiyama; Kazuhiko Ino; Seiji Nomura; Akihiro Nawa; Shigehiko Mizutani; Fumitaka Kikkawa
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Publication Detail:
Type:  Journal Article    
Journal Detail:
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:
Created Date:  2006-01-24     Completed Date:  2007-05-29     Revised Date:  2009-11-24    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1390-4     Citation Subset:  IM    
Affiliation:
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan. shiba@med.nagoya-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / 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:
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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