Placental leucine aminopeptidase (P-LAP) expression is associated with chemosensitivity in human endometrial carcinoma.
OBJECTIVE
Although treatment for advanced or recurrent endometrial carcinoma has improved over recent years with the introduction of paclitaxel- and platinum-based chemotherapy, in most, the disease remains incurable because of resistance to chemotherapy. In the previous study, we have shown that placental leucine aminopeptidase (P-LAP) is associated with poor prognosis. The objective of this study was to determine whether P-LAP expression affects the chemosensitivity in endometrial carcinoma patients.


METHODS
Here, we investigated the effect of P-LAP to response for paclitaxel and carboplatin in advanced and recurrence endometrial carcinoma. Furthermore, we transfected P-LAP cDNA into endometrial carcinoma cells (AMEC) and investigated cell growth and apoptosis by paclitaxel or carboplatin.


RESULTS
In 15 of 17 patients, P-LAP was positive. Twelve of seventeen patients were evaluable for response. Among the eight patients strongly positive for P-LAP, only two patients (25%) showed PR. However, all four patients who were weakly positive for P-LAP showed either complete response (CR) or partial response (PR). P-LAP overexpressor (P-LAP2 and P-LAP8) and a vector control were used to assay chemosensitivity. P-LAP2 clone displayed a 1.7-fold increase in IC(50) against paclitaxel and carboplatin when compared with the vector control, and P-LAP8 clone displayed a 1.6-fold increased in IC(50) against paclitaxel and carboplatin when compared with V1. Compared to vector control cells, apoptotic effect by carboplatin treatment was clearly inhibited in P-LAP2 and P-LAP8 cells. Carboplatin, 10(-6) M, induced the 12.5-fold rate of apoptosis compared to that without treatment at 48 h in vector control cells. However, in P-LAP2 and P-LAP8 clones, 10(-6) M carboplatin induced only 3.2- and 5.1-fold rates of apoptosis, respectively, compared to that of without treatment.


CONCLUSIONS
P-LAP was suggested to be involved in reducing chemosensitivity and may be a therapeutic target in endometrial carcinoma.
Shibata
Kiyosumi
K
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan. shiba@med.nagoya-u.ac.jp <shiba@med.nagoya-u.ac.jp>
Kikkawa
Fumitaka
F
Kondo
Chihiro
C
Mizokami
Yayoi
Y
Kajiyama
Hiroaki
H
Ino
Kazuhiko
K
Nomura
Seiji
S
Mizutani
Shigehiko
S
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D010122:Cystinyl Aminopeptidase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000201:enzymology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D014162:Transfection
D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D017239:Paclitaxel; D002945:Cisplatin