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A novel role for placental leucine aminopeptidase (P‐LAP) as a determinant of chemoresistance in endometrial carcinoma cells
Author(s) -
Kondo Chihiro,
Shibata Kiyosumi,
Terauchi Mikio,
Kajiyama Hiroaki,
Ino Kazuhiko,
Nomura Seiji,
Nawa Akihiro,
Mizutani Shigehiko,
Kikkawa Fumitaka
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21509
Subject(s) - carboplatin , apoptosis , transfection , cancer research , downregulation and upregulation , caspase , cisplatin , paclitaxel , cell culture , biology , microbiology and biotechnology , programmed cell death , medicine , chemotherapy , biochemistry , gene , genetics
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. © 2005 Wiley‐Liss, Inc.