PubMed Health⌕ Search

Biomedical subjects

Fumitaka Kikkawa

Publications and source records attributed to Fumitaka Kikkawa.

At least 37 records · Page 2Linked to original sources
PubMed2005

Placental leucine aminopeptidase might regulate the effects of oxytocin with resolution in endothelial cells.

BACKGROUND: Oxytocin (OT) is known to cause vascular relaxation via nitric oxide (NO) production and proliferation of endothelial cells. Previously we revealed that human umbilical vascular endothelial cells (HUVECs) expresses placental leucine aminopeptidase (P-LAP)/insulin regulated aminopeptidase (IRAP), which becomes translocation to the cell surface on activation of oxytocin receptor (OTR). However, the physiological roles of P-LAP in HUVECs have not been elucidated. MATERIAL/METHODS: Actions of OT on HUVECs transfected with a copy of the human P-LAP gene were therefore examined with a focus on changes in parameters linked to OTR such as calcium mobilization, NO production and cell proliferation. RESULTS: Cell surface P-LAP activity was significantly elevated (approximately 3 fold) in P-LAP overexpressing-HUVECs and overexpression of P-LAP resulted in remarkable inhibition of OT effects on HUVECs such as cell proliferation, [Ca2+]i, and NO production. CONCLUSIONS: These findings suggested that P-LAP on the plasma membrane in HUVECs regulates the effects of OT with resolution around OTR.

Calcium↗
PubMed2005

Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination.

PURPOSE: Angiotensin II is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptors (AT1R). The present study examined AT1R expression in human ovarian carcinoma and attempted to determine whether AT1R blocker could suppress the tumor progression. EXPERIMENTAL DESIGN: Expression of AT1R, vascular endothelial growth factor (VEGF), and CD34 was immunohistochemically analyzed in ovarian tumor tissues (n=99). Effects of AT1R blocker on invasive potential and VEGF secretion in ovarian cancer cells were examined in vitro. Effects of AT1R blocker in vivo were evaluated in a mouse model of peritoneal carcinomatosis. RESULTS: AT1R was expressed in 57 of 67 (85%) invasive ovarian adenocarcinomas and 12 of 18 (66%) borderline malignant tumors but in only 2 of 14 (14%) benign cystadenomas. In invasive carcinomas, VEGF expression intensity and intratumor microvessel density were significantly higher in cases that were strongly positive for AT1R (n = 37) compared with those in cases weakly positive (n = 20) or negative (n = 10) for AT1R. Angiotensin II significantly enhanced the invasive potential and VEGF secretion in AT1R-positive SKOV-3 ovarian cancer cells, both of which were completely inhibited by the AT1R blocker candesartan. Administration of candesartan into SKOV-3-transplanted athymic mice resulted in the reduction of peritoneal dissemination, decreased ascitic VEGF concentration, and suppression of tumor angiogenesis. CONCLUSIONS: AT1R is functionally expressed in ovarian carcinoma and involved in tumor progression and angiogenesis. AT1R blockade therapy may become a novel and promising strategy for ovarian cancer treatment.

Adenocarcinoma↗
PubMed2005

Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo.

Recently, numerous studies have shown that endothelin-1 (ET-1) is expressed in ovarian carcinoma and that ET-1 selectively acts as an autocrine or paracrine growth factor through the endothelin A receptor (ET(A)R), and is involved in cell proliferation, invasiveness, neovascularization, and prevention of apoptosis. Neutral endopeptidase 24.11 (NEP) is a cell surface aminopeptidase with a ubiquitous expression and is capable of degrading a number of bioactive peptides including ET-1. Our previous report showed that stromal NEP expression in ovarian carcinoma was down-regulated as the histologic grade advanced. Here, we confirmed that NEP was expressed in tumor cells as well as stromal tissues in ovarian carcinoma, and investigated the functions of NEP in this carcinoma. We showed that there was a significant decrease in cell proliferation and invasiveness with a reduction in the concentration of ET-1 in the conditioned medium on the NEP overexpression of NEP in ovarian carcinoma cells. In addition, the overexpression of NEP enhanced susceptibility to paclitaxel, resulting in an increased occurrence of apoptotic morphologic change. Furthermore, tumorigenesis was reduced in vivo with the overexpression of NEP, down-regulation of both matrix metalloproteinase-2, and vascular endothelial growth factor expression. This evidence suggests that NEP functionally suppresses the progression of ovarian carcinoma and further study of this enzyme may reveal an effective way to target ET-1 for the treatment of this carcinoma.

Apoptosis↗
PubMed2005

Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma.

OBJECTIVE: It has recently been appreciated that a local autocrine or paracrine renin-angiotensin system (RAS) may exist in a number of tissues. Angiotensin II (AngII) is a potent RAS-derived vasoconstrictor peptide, and it is involved in tumor angiogenesis. We have cloned human adipocyte-derived leucine aminopeptidase (A-LAP), which degrades Ang II. This study investigated whether the expression of A-LAP, Ang II, angiotensin type I receptor (AT1R) and vascular endothelial growth factor (VEGF) correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 94 primary endometrial carcinomas were stained for A-LAP, AngII, AT1R and VEGF using each antibody. Disease-free survival (DFS) and other clinicopathologic characteristics were analyzed according to the intensity of each staining. RESULTS: Of 94 cases, 91 (96.8%) showed specific A-LAP immunostaining. A-LAP expression demonstrated negative correlations with myometrial invasion (p = 0.01) and vascular infiltration (p = 0.01). Of 94 cases, 77 (81.9%) showed specific AngII immunostaining. We found a positive correlation between AngII expression and surgical stage (p = 0.01). Of 94 cases, 56 (59.6%) showed specific AT1R immunostaining and 73 (77.7%) specific VEGF immunostaining. We found a positive correlation between VEGF expression and lymph node metastasis (p = 0.05). AngII and AT1R expression predicted a significantly poorer prognosis. Contrarily, A-LAP expression indicated a significantly more favorable prognosis in endometrial endometrioid adenocarcinoma patients. Multivariate analysis demonstrated that A-LAP expression (odds ratio, 0.12; 95% confidence interval, 0.025-0.618; p = 0.01) was an independent prognostic factor. CONCLUSIONS: In this study, we demonstrated the existence of local RAS and A-LAP in endometrial endometrioid adenocarcinoma as prognostic predictors of clinical outcome. These findings suggest that the assessment of RAS and A-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.

Adipocytes↗
PubMed2005

Possible involvement of aminopeptidase A in hypertension and renal damage in Dahl salt-sensitive rats.

BACKGROUND: Although aminopeptidase A (APA), which is abundant in the kidneys, is responsible for metabolizing angiotensin II (Ang II), its association with salt sensitivity remains uncertain. We aimed to clarify the involvement of APA in salt-induced hypertension and renal damage. METHODS: Male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats were fed low-salt (0.3%) or high-salt diet (8%) from 6 weeks of age for 12 weeks. Tail-cuff-measured blood pressure (BP), renal APA activity, renal Ang II levels, histologic renal damage, and APA immunoreactivity were periodically examined. RESULTS: Systolic BP progressively increased only in DS rats given the high-salt diet (DS-8% rats). The DR-8% rats had approximately 3-fold higher renal APA activity than the rats given the low-salt diet (DR-0.3% rats) during the maintenance on the high-salt diet. However, although DS-8% rats also had 2.5-fold higher renal APA activity than DS-0.3% rats at 10 weeks, continuing the high-salt diet afterward suppressed the activity in DS-8% rats below the levels observed in DS-0.3% rats. High-salt diet reduced renal Ang II levels by 30% in DR rats, whereas it showed a small and nonsignificant decrease in DS rats. The number of injured glomeruli was markedly elevated in DS-8% rats after 10 weeks. The APA immunostaining in DS-8% rats was enhanced in glomeruli displaying mild damage, diminished in the severely injured glomeruli, and absent in lesions with hyalinization. CONCLUSIONS: High-salt diet in DS rats increased renal APA activity, although renal injury remained mild, but then reduced it along with the progression of glomerulosclerosis, suggesting that reduced APA activity may be involved in the deterioration of salt-induced hypertension and renal injury.

Angiotensin II↗
PubMed2005

Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia.

OBJECTIVE: Increased glucose consumption is a characteristic of malignant cells. Glucose is transported into the cell via facilitative glucose transporters, which are known to be members of a supergene family. The insulin-responsive GLUT4 isoform is expressed almost exclusively in insulin target tissues. P-LAP is a cell surface aminopeptidase, and is a synonym for oxytocinase. P-LAP is also referred to as insulin-regulated membrane aminopeptidase (IRAP) associated with GLUT4-containing vesicle. The authors evaluated P-LAP and GLUT4 expression in benign, borderline, and malignant ovarian epithelia. METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 11 patients with benign serous or mucinous cystadenomas, 14 patients with serous or mucinous borderline tumors, and 80 patients with epithelial-ovarian adenocarcinomas (29 serous, 17 endometrioid, 14 mucinous, and 20 clear cell adenocarcinomas) were stained for P-LAP and GLUT4 using each polyclonal antibody. Expressions of P-LAP and GLUT-4 in ovarian cancer cells were detected by Western blotting. RESULTS: P-LAP immunoreactivity was detected in 2 of 11 benign cystadenomas. None of the 11 benign ovarian tumors showed any immunoreactivity for GLUT4. Seven of 14 borderline tumors demonstrated P-LAP immunoreactivity, while 5 of 14 borderline tumors demonstrated GLUT4 immunoreactivity. P-LAP was expressed in 23 of 29 in serous, 15 of 17 endometrioid, 13 of 14 mucinous, and all clear-cell adenocarcinomas. The tendency toward increased P-LAP expression with advancing grade was observed in serous adenocarcinomas. GLUT4 was expressed in 13 of 29 serous, 13 of 17 endometrioid, 13 of 14 mucinous, and 18 of 20 clear-cell adenocarcinomas. In invasive carcinomas, there was a direct correlation between P-LAP immunoreactivity and GLUT4 immunoreactivity (correlation coefficient [r] = 0.58; P < 0.01). Furthermore, P-LAP overexpression in SKOV3 cells induced the GLUT4 expression. CONCLUSIONS: P-LAP and GLUT4 are available not only for the evaluation of ovarian epithelial malignancy, but also as targets for molecular therapy. Further study to investigate the roles of P-LAP and GLUT4 in ovarian carcinoma is needed.

Adult↗
PubMed2005

[Choriocarcinoma treatment: goal and issues].

The success of choriocarcinoma treatment in Japan is over 90% at the present time. As for the first contribution, chemotherapeutic progress contributed to this success greatly. The next contribution is establishment of the registration system of administration of the hydatidiform mole patients, since the course of choriocarcinoma in most cases is hydatidiform mole --> invasive mole --> choriocarcinoma. When treatment is begun by preventive measures for benign tumors at the very onset of the invasive hydatidiform mole, there are fewer choriocarcinoma onsets. Moreover, discovery of choriocarcinoma in the initial stages contributes to a better prognosis. However, following abortion or normal childbirth, different measures may be necessary. No problems were found with patients once treated for invasive hydatidiform mole in connection with current problems involving post-treatment pregnancy or delivery. However, in cases of pregnancy or abortion after choriocarcinoma treatment done with multi-cancer agents strongly, heart malformations are seen in some newborns, and how to preserve egg cells may pose a problem at the time of anti-cancer agent administration.

Choriocarcinoma↗
PubMed2004

Dipeptidyl peptidase IV in tumor progression.

Dipeptidyl peptidase IV (DPPIV) is a 110-kDa glycoprotein with ubiquitous expression. Several recent studies have shown that DPPIV affects tumor progression in several human malignancies. We found that ovarian carcinoma cell lines with higher DPPIV expression showed less invasive potential. Furthermore, introduction of DPPIV cDNA into SKOV3 cells (SKDPIV), derived from serous cystadenocarcinoma showing little DPPIV expression, caused a significant decrease in both migration and invasive potential. In addition, nude mice inoculated with SKDPIV cells showed significantly less peritoneal dissemination and longer survival time than those inoculated with parental or vector-transfected cells. We further examined the mechanisms of anti-invasive ability of DPPIV. The expression of E-cadherin was positively correlated with DPPIV expression among five independent ovarian carcinoma cell lines. The SKDPIV cells showed enhanced expression of E-cadherin with a cellular morphological change from a fibroblastic and motile phenotype to an epithelial phenotype compared to parental and MOCK cells. In addition, matrix metalloproteinase 2 (MMP-2) and membrane type 1 matrix metalloprotease (MT1-MMP), which are important markers associated with invasive and metastatic potential, were remarkably reduced in SKDPIV cells. In contrast, tissue inhibitors of matrix metalloproteinases (TIMPs) were enhanced by DPPIV transfection. These findings imply that DPPIV may functionally suppress peritoneal dissemination and progression of ovarian carcinoma by regulating the expression levels of several molecules associated with carcinoma cell invasion and progression.

Adenocarcinoma↗
PubMed2004

Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha.

A previous report demonstrated that AP-2alpha favors the survival of ovarian cancer patients by clinical findings. However, the functional roles of AP-2alpha in human ovarian cancers have not been determined. To clarify the roles, we overexpressed AP-2alpha in SKOV3 human ovarian cancer cells, which originally possess little AP-2alpha. AP-2alpha overexpression changed cell morphology from spindle to epithelioid type and suppressed cell proliferation and invasion, which would be partially correlated with decreased phosphorylation levels of the erbB2, Akt and ERK pathways, increased E-cadherin and reduced pro-matrix metalloproteinase-2 levels. Moreover, nude mice intraperitoneally injected with AP-2alpha-overexpressing cells survived longer than those with neo-transfected cells. The present data represent the first direct evidence that AP-2alpha plays a tumor suppressive role in ovarian cancer.

Cadherins↗
PubMed2004

Stromal cell-derived factor-1alpha-induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma.

CD26/dipeptidylpeptidase IV (DPPIV) is a 110 kD membrane-bound extracellular peptidase with ubiquitous expressions, and has a variety of functional properties in the development of human malignancies as well as T-cell biology. According to recent reports, stromal cell derived factor-1alpha (SDF-1alpha), which is a good substrate for CD26/DPPIV, is expressed in various solid tumors and is involved in tumor development or metastasis. We investigated the expression of SDF-1alpha and its corresponding receptor, CXCR4, in human endometrial carcinoma (EMCA) tissues and the function of SDF-1alpha on EMCA cells with its regulation by CD26/DPPIV. We demonstrated that SDF-1alpha and CXCR4 were expressed in human EMCA, and these immunoreactivities were significantly low in Grade 3 EMCA, which was similar to that of CD26/DPPIV, compared to those in Grade 1 and Grade 2. Additionally, exogenous SDF-1alpha concentration was significantly lower in CD26/DPPIV-transfected EMCA cells than that in vector-transfected cells. Moreover, exogenous SDF-1alpha significantly stimulated cell proliferation in vector-transfected cells in a concentration dependent manner. In contrast, in CD26/DPPIV-transfected cells, there was no apparent effect on proliferation shown by the addition of exogenous SDF-1alpha. This is the first report showing a direct link between the SDF-1alpha/CXCR4 pathway with CD26/DPPIV in solid tumors, suggesting that CD26/DPPIV is likely to directly modulate various SDF-1alpha induced functions.

Adenocarcinoma↗
PubMed2004

Oxytocin inhibits the progression of human ovarian carcinoma cells in vitro and in vivo.

The neurohypophyseal nonapeptide oxytocin (OT) is involved in many biologic functions and regulation of cell proliferation under both physiologic and neoplastic conditions. In some cases, OT exhibits an oxytocin receptor (OTR)-mediated antiproliferative effect on cancer cells. In this study, we examined the effects of OT on ovarian carcinoma progression in vitro and in vivo. We investigated the inhibitory effects of OT on cell growth, invasion and migration in vitro. Furthermore, we examined the OT effects in vivo ovarian carcinoma model. We demonstrated OTR expressions in the large majority of ovarian carcinoma tissues, and OT inhibited not only proliferation but also migration and invasion in ovarian carcinoma cells in vitro. Furthermore, we examined the mechanisms of the antiinvasive ability of OT. Secretion of matrix metalloproteinase 2 was slightly inhibited by 10(-7) M OT, while treatment with 10(-7) M OT for 24 hr remarkably enhanced the expression of E-cadherin. In addition, our in vivo study showed that intraperitoneal administration of OT resulted in the reduction of intraperitoneal dissemination of ovarian carcinoma cells. Mean tumor burden in the OT-treated group (0.2 +/- 0.11 g) was significantly (p < 0.05) less than that of physiologic saline-treated group (0.5 +/- 0.54 g). This evidence implies that OT may functionally suppress peritoneal dissemination in ovarian carcinoma.

Animals↗
PubMed2004

Insulin stimulates placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase expression in BeWo choriocarcinoma cells.

Placental leucine aminopeptidase (P-LAP), a cystine aminopeptidase that is identical to insulin-regulated membrane aminopeptidase, hydrolyzes oxytocin, which results in the loss of oxytocin activity. We previously isolated genomic clones containing the human P-LAP promoter region, which included two sites homologous to the 10-bp-insulin responsive element (IRE) that was identified on the phosphoenolpyruvate carboxinase gene. We therefore postulated that insulin regulates P-LAP expression via these IREs and investigated this notion using BeWo choriocarcinoma trophoblastic cells cultured in the presence of insulin. Insulin increased P-LAP activity in a time- and dose-dependent manner. Physiological concentrations of insulin at 10(-7) M exhibited the most potent effect on P-LAP activity. Western blotting demonstrated that 10(-7) M insulin increased P-LAP protein levels. Semi-quantitative RT-PCR and Southern blotting showed that insulin also increased P-LAP mRNA, which was abrogated by prior exposure to cycloheximide. Luciferase assay did not reveal any regulatory regions within 1.1 kb upstream of the P-LAP gene that could explain the insulin-induced P-LAP mRNA accumulation. These findings indicate that insulin induces P-LAP expression in trophoblasts, and that it acts via de novo synthesis of other proteins, which partially contradicts our initial hypothesis.

Base Sequence↗
PubMed2004

ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase.

Placental leucine aminopeptidase (P-LAP), a type-II transmembrane protease responsible for oxytocin degradation during pregnancy, is converted to a soluble form through proteolytic cleavage. The goal of this study was to determine the nature of the P-LAP secretase activity. The hydroxamic acid-based metalloprotease inhibitors GM6001 and ONO-4817 as well as the TNF-alpha protease inhibitor-2 (TAPI-2) reduced P-LAP release, while tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, which are matrix metalloproteinase inhibitors, had no effect on P-LAP release in Chinese hamster ovary (CHO) cells stably overexpressing P-LAP, thus indicating possible involvement of ADAM (a disintegrin and metalloproteinase) members in P-LAP shedding. Furthermore, overexpression of ADAM9 and ADAM12 increased P-LAP release in P-LAP-CHO transfectants. Immunohistochemical analysis in human placenta demonstrated strong expression of ADAM12 in syncytiotrophoblasts, while little expression of ADAM9 was detected throughout the placenta. Our results suggest ADAM members, at least including ADAM12, are involved in P-LAP shedding in human placenta.

Animals↗
PubMed2004

Activation of invasiveness of cervical carcinoma cells by angiotensin II.

OBJECTIVE: Angiotensin II recently has been reported to promote the growth of several kinds of cells. In this study, we investigated the effect of angiotensin II on cervical carcinoma cells. STUDY DESIGN: The expression of angiotensin II type I receptor was examined by immunohistochemistry in normal and neoplastic cervical tissues. Invasion assay was examined in Siha cells (cervical squamous cell carcinoma) and vascular endothelial growth factor levels were assayed with a vascular endothelial growth factor enzyme-linked immunosorbent assay kit. RESULTS: Mean staining intensity level was stronger in invasive carcinoma cells than in normal, dysplasia, and carcinoma in situ tissues. Angiotensin II induced the secretion of vascular endothelial growth factor from Siha cells. Furthermore, angiotensin II promoted the invasive potential of Siha cells. These effects were reversed by the addition of anti-human vascular endothelial growth factor antibody and candesartan (antagonist of angiotensin II type I receptor). CONCLUSION: Angiotensin II is involved in the progression of cervical carcinoma, because it induces the secretion of vascular endothelial growth factor through angiotensin II type I receptor, which results in the increased invasiveness of carcinoma cells.

Angiotensin II↗
PubMed2004

Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births.

OBJECTIVES: The outcomes of patients with choriocarcinoma treated with fertility-preserving techniques and the children born to patients subjected to combined chemotherapy were examined retrospectively. METHODS: We treated 191 patients with choriocarcinoma from 1965 through 2001. Of these, 62 were treated with fertility-preserving techniques (50 were cured and 12 died) and 129 with hysterectomy (88 were cured and 41 died). RESULTS: Between 1965 and 1972, survival in the hysterectomy group increased. Thereafter, no significant differences between the two groups were observed. Subsequently, the number of cases with uterus preservation increased and occupied about two thirds of all cases. There were no significant differences in patient survival between the two groups by FIGO stage, although the data tended to support uterus preservation. Of the 50 patients who underwent fertility-preserving treatment for choriocarcinoma, 23 conceived for a total of 43 pregnancies. Thirty-four children were born without congenital malformations. However, two babies were born with ventricular septal defect (VSD) and one with tetralogy of Fallot (TOF) (3/34; 8.8%). The three children were the second child born after combination chemotherapy. The total dose of Methotrexate (MTX) was higher in patients who delivered a child with a heart anomaly (P < 0.02). CONCLUSIONS: Patients treated with fertility-preserving modalities had comparable survival rates to those undergoing hysterectomy at more recent time points. The incidence of congenital heart abnormalities was higher for patients undergoing combined chemotherapy than in the general population. The influence of anti-cancer agents on oocytes should be incorporated into any treatment plans for patients wishing to bear children.

Adult↗
PubMed2004

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.

Aged↗
PubMed2004

Regulation of aminopeptidase A expression in cervical carcinoma: role of tumor-stromal interaction and vascular endothelial growth factor.

We previously demonstrated that aminopeptidase A (APA), a membrane-bound metallopeptidase degrading bioactive peptides such as angiotensin II (Ang II), is expressed in neoplastic lesions of the uterine cervix, and that its expression is upregulated as the lesion progresses from cervical intraepithelial neoplasms (CIN) toward invasive squamous cell carcinomas (SCC). The present study investigated the regulatory mechanisms involved in APA expression and its potential role in cervical carcinoma. Immunohistochemical staining in high-grade CIN and SCC tissues showed that APA was strongly expressed at the edge of lesions adjacent to cervical stromal cells. Fluorescence-activated cell sorting analysis demonstrated that cell surface APA expression was extremely low in three human SCC cell lines, SiHa, TCS and CaSki, under basal conditions. However, both contact and noncontact cocultures with human cervical fibroblasts resulted in the induction of APA expression in these SCC cells. APA expression was also induced in vivo when TCS cells were subcutaneously inoculated into nude mice. Furthermore, APA expression and enzymatic activity were enhanced by addition of the conditioned medium (CM) from fibroblast culture, but not by heat-treated CM. Among the various cytokines tested, vascular endothelial growth factor (VEGF) significantly increased APA activity, and induction of APA by the fibroblast CM was partly inhibited by anti-VEGF neutralizing antibody. Finally, APA cDNA-transfected APA-overexpressing TCS cells significantly reduced the Ang II-induced cell invasion ability as compared with parental or control vector-transfected TCS cells, although there was no significant difference in cellular proliferation among them. These results suggested the importance of tumor-stromal interaction for the regulation of APA expression in the microenvironment of cervical carcinoma and the potential role for this peptidase in regulating tumor invasion through inactivation of Ang II activity.

Angiotensin II↗