Placental leucine aminopeptidase (P-LAP) expression is associated with chemosensitivity in human endometrial carcinoma

Shibata, Kiyosumi; Kikkawa, Fumitaka; Kondo, Chihiro; Mizokami, Yayoi; Kajiyama, Hiroaki; Ino, Kazuhiko; Nomura, Seiji; Mizutani, Shigehiko

doi:10.1016/j.ygyno.2004.07.054

Cited by 9 publications

(6 citation statements)

References 17 publications

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“…Furthermore, a recent study showed that the tumor suppressor p53 down regulates GLUT1 and GLUT4 gene expression [18]. In previous studies, we demonstrated that P-LAP/IRAP was a poor prognostic factor of endometrial cancer, and that P-LAP/IRAP was involved in proliferation, anticancer agent resistance, and anti-apoptosis by a P-LAP/IRAP gene transfer experiment [11,12,19]. In this study, we showed the tendency of an increased GLUT4 immunoreactivity with the advancement of the tumor grade, and this tendency was similar to the results of P-LAP/IRAP.…”

Section: Discussionmentioning

confidence: 99%

P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

et al. 2007

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Background: Hyperglycemia or hyperinsulinemia contributes to poorer endometrial cancer survival. It was shown that P-LAP/IRAP translocates to the plasma membrane in response to insulin stimulation. Recently, we demonstrated that P-LAP/IRAP is associated with a poor prognosis in endometrial adenocarcinoma patients. The aim of this study was to examine 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.

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Section: Discussionmentioning

confidence: 99%

P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

et al. 2007

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“…Currently not much detail is known about the function and the distribution of expression for LAP3. Interestingly placental leucine aminopeptidase (P-LAP) has been linked specifically with EmCa, and an increased expression level of P-LAP is associated with a poor prognosis (52). However, a BLAST (Basic Local Align-ment Search Tool) search between the LAP3 and P-LAP amino acid sequence returned no significant homology, thus making LAP3 a potentially novel marker for endometrial cancer.…”

Section: Endometrial Carcinoma Biomarker Discovery and Verificationmentioning

confidence: 99%

Endometrial Carcinoma Biomarker Discovery and Verification Using Differentially Tagged Clinical Samples with Multidimensional Liquid Chromatography and Tandem Mass Spectrometry

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et al. 2007

Molecular & Cellular Proteomics

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. (2005) Search for cancer markers from endometrial tissues using differentially labeled tags iTRAQ and cleavable ICAT with multidimensional liquid chromatography and tandem mass spectrometry. J. Proteome Res. 4, 377-386) to discriminate malignant and benign endometrial tissue samples was verified in a 40-sample iTRAQ (isobaric tags for relative and absolute quantitation) labeling study involving normal proliferative and secretory samples and Types I and II endometrial cancer samples. None of these proteins had the sensitivity and specificity to be used individually to discriminate between normal and cancer samples. However, a panel of pyruvate kinase, chaperonin 10, and ␣ 1 -antitrypsin achieved the best results with a sensitivity, specificity, predictive value, and positive predictive value of 0.95 each in a logistic regression analysis. In addition, three new potential markers were discovered, whereas two other proteins showed promising trends but were not detected in sufficient numbers of samples to permit statistical validation. Differential expressions of some of these candidate biomarkers were independently verified using immunohistochemistry. Molecular & Cellular Proteomics 6:1170 -1182, 2007.Differential tagging with isotopic reagents, such as ICAT (1) or the more recent variation that uses isobaric tagging reagents, iTRAQ 1 (Applied Biosystems, Foster City, CA), followed by multidimensional LC and MS/MS analysis is quickly being recognized as one of the more powerful methodologies in the search for biomarkers for various disease states. Our recent studies using both ICAT and iTRAQ reagents as means to facilitate the identification and relative quantification of proteins from endometrial tissue homogenates have resulted in some interesting potential cancer markers (PCMs) (2, 3). Those studies, however, were performed on small sample sets. This study describes the results of a more detailed investigation using a larger cohort of 40 samples and the iTRAQ technology and was aimed at validating the earlier results as well as expanding the panel of biomarkers.Endometrial carcinoma (EmCa), a cancer of the lining of the uterus, is the fourth most common cancer in Canadian women.2 Current methods of diagnosis rely on invasive techniques (biopsy and curettage), and no screening is available. A panel of biomarkers that helps in early diagnosis would, therefore, be useful especially for high risk groups, e.g. women who are on tamoxifen treatment or have hereditary nonpolyposis colorectal cancer syndrome. Although the eventual diagnostic testing for such biomarkers would be most facile from bodily fluids, such as blood or urine, the iTRAQ experiments performed thus far have been on resected From the Departments of ‡Chemistry, §Biology, and ʈMathematics

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“…3 In our study, we investigated the mechanism. Most cases of advanced endometrial carcinoma are resistant to anticancer drugs, and to improve the prognosis of advanced endometrial carcinoma, the mechanism involved in anticancer drug resistance must be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Since chemotherapy play a role in the management of endometrial carcinoma in patients with advanced disease, we focused on the relation between the expression of P-LAP and chemosensitivity. In our previous study, we showed that P-LAP expression is associated with chemosensitivity in endometrial carcinoma.…”

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confidence: 99%

“…In our previous study, we showed that P-LAP expression is associated with chemosensitivity in endometrial carcinoma. 3 Inhibition of apoptosis can influence the response of tumor cells to anticancer therapy. 4 It is reasonable to suggest that the lowered response of advanced or recurrent case to chemotherapeutic regimens, when compared to the response rate obtained for the same disease at initial presentation or before dissemination, is because the tumor has acquired the antiapoptotic gene.…”

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A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells

et al. 2005

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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. ' 2005 Wiley-Liss, Inc.

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Placental leucine aminopeptidase (P-LAP) expression is associated with chemosensitivity in human endometrial carcinoma

Cited by 9 publications

References 17 publications

P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

Endometrial Carcinoma Biomarker Discovery and Verification Using Differentially Tagged Clinical Samples with Multidimensional Liquid Chromatography and Tandem Mass Spectrometry

A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells

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