Differential sensitivity of human endometrial carcinoma cells with different PTEN expression to mitogen-activated protein kinase signaling inhibits and implications for therapy.

PURPOSE: Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the mitogen-activated protein kinase (MAPK) signaling pathway appear to play a major role in the tumor cell's proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore whether sensitivity to p38MAPK inhibitors are specifically due to status of PTEN in endometrial cancer cells. METHODS: We developed a series of endometrial cancer cell lines with different PTEN expressions (Ishikawa, RL-952, HEC-1B and HEC-1A cells) or introduced the wild-type PTEN and PTEN-siRNA in four endometrial cancer cells to change its PTEN expression with a p38MAPK inhibitor, SB203580 for 2 days. Cell proliferation, cell apoptosis, and cell cycle distribution were studied, and activation of AKT, ATF-2, and p38MAPK was examined by Western blotting. RESULTS: In cultivated PTEN-deficient endometrial cancer cells, in addition to an activation of AKT, a phosphorylation of p38MAPK and ATF-2 was evident, while PTEN-positive endometrial cancer cells lacked AKT activation but revealed a reduced expression of p-p38MAPK and p-ATF-2. These PTEN-deficient endometrial cancer cells demonstrated an increased sensitivity to the anti-proliferative effects induced by SB203580 compared with the PTEN-positive endometrial cancer cells, which corresponded to alterations in cell cycle response and cell apoptosis. CONCLUSIONS: PTEN-deficient endometrial cancer cells exhibit higher p38MAPK activity, and genetic studies demonstrate that p38MAPK functions dependently of AKT. Furthermore, PTEN loss sensitizes cells to p38MAPK inhibition in endometrial carcinoma cells. These findings indicate that inhibitors of p38MAPK have the potential to be effective in the treatment of endometrial cancer patients with PTEN-deficient tumors and should be evaluated in this setting.

[Effect of signal transduction inhibitors on human endometrial carcinoma cells with differential PTEN gene expression].

OBJECTIVE: To investigate the apoptotic and proliferation effects of signal transduction inhibitors on human endometrial carcinoma cells with different PTEN gene expression. METHODS: PTEN antisense oligonucleotide and pcDNA3.1/PTEN vector contained PTEN gene were transfected into endometrial carcinoma cells (HEC-1A and Ishikawa). The expression of PTEN protein was detected by confocal spectral microscopy. The endometrial carcinoma cells (HEC-1A, HEC-1A-PTEN-null, Ishikawa, Ishikawa-PTEN) were treated with signal transduction inhibitors, RG-14620, SB203580 (SB) and rapamycin, respectively. Cell apoptosis morphology, cell apoptosis and cell cycle were detected by Hoechst 33258 staining and flow cytometry. Cell viability was determined by methyl thiazolyl tetrazolium assay. RESULTS: The PTEN protein expression in two endometrial carcinoma cells (Ishikawa, HEC-1A) was exchanged by PTEN antisense oligonucleotide blocked and pcDNA3.1/PTEN stable transfected. After treated with RG-14620, SB and rapamycin, marked morphological changes of apoptosis were observed in HEC-1A-PTEN-null and Ishikawa cells. The cell apoptosis of HEC-1A-PTEN-null and Ishikawa cells exposed to SB were significantly increase [(31.6 +/- 0.8)% and (37.8 +/- 0.8)%, respectively], the G(1) phase cells were increased to (84.1 +/- 3.2)% and (87.5 +/- 1.9)%. While cell viability was significantly decreased in HEC-1A-PTEN-null and Ishikawa cells, the cell viability of HEC-1A-PTEN-null and Ishikawa cells exposed to SB were (54.0 +/- 2.1)% and (49.0 +/- 1.7)%. CONCLUSION: Loss of PTEN in endometrial carcinoma cells may improve the G(1) phase cells and apoptotic effects, inhibit the cell proliferation, which due to the sensitivity of cells to related signal transduction inhibitors.

Misoprostol in labour induction of term pregnancy: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of misoprostol in term labour induction. DATA SOURCES: Data from published English and Chinese literatures about misoprostol in term labour induction were identified from Medline and CBMdisk (using the search terms "misoprostol" and "labour induction") before 2001; hand searches of reference lists of original studies and reviews (including meta-analyses) and contact with investigators in this field before 2001. STUDY SELECTION: Studies were included if they had data on misoprostol and labour induction. Altogether 623 articles were found and 124 were admitted, including 19,287 cases. DATA EXTRACTION: Data were collected on efficacy and incidence of side-effects of misoprostol and oxytocin. Data were checked for consistency within the published articles and converted into a standard format for incorporation into a central database. DATA SYNTHESIS: The average successful induction rate, rates of caesarean section; incidence of tachysystole, hypertonus of uterus and precipitous labour, and rates of meconium stained amniotic fluid between the misoprostol and oxytocin groups were significantly different (P < 0.05). There were no significant differences between the two groups concerning the average interval from the administration of misoprostol and oxytocin to the onset of labour, duration of the total stage of labour, incidence rate of foetal distress, neonatal asphyxia (1-minute Apgar score < and= 7), postpartum haemorrhage or amount of blood loss in postpartum. CONCLUSIONS: Misoprostol is a superior agent over oxytocin on the induction of term labour, but its application might increase the risk of precipitous labour, abnormal uterine contractions or meconium stained amniotic fluid. Therefore, the dosages and regimens of the agent need further investigation.