Epithelial ovarian cancer is the most common and lethal gynecological cancer in USA and around the world, causing major mortality annually. In the current study, we investigated the potential anti-ovarian cancer activity of WYE-132, a mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor. Our results showed that WYE-132 potently inhibited proliferation of primary and established human ovarian cancer cells. Meanwhile, WYE-132 induced caspase-dependent apoptosis in ovarian cancer cells. At the molecular level, WYE-132 blocked mTORC1/2 activation and inhibited expression of mTOR-regulated genes (cyclin D1 and hypoxia-inducible factor 1α). Interestingly, introducing a constitutively active AKT (caAKT), which restored mTORC1/2 activation in WYE-132-treated ovarian cancer cells, only mitigated (but not abolished) WYE-132-mediated growth inhibition and apoptosis. Further studies showed that WYE-132 inhibited sphingosine kinase-1 (SphK1) activity, leading to pro-apoptotic ceramide production in ovarian cancer cells. Meanwhile, WYE-132-induced cytotoxicity against ovarian cancer cells was inhibited by sphingosine-1-phosphate (S1P) but was aggravated by SphK1 inhibitor SKI-II or C6 ceramide. In vivo, WYE-132 inhibited ovarian cancer cell growth, and its activity was further enhanced when co-administrated with paclitaxel (Taxol). These results demonstrate that WYE-132 inhibits ovarian cancer cell proliferation through mTOR-dependent and mTOR-independent mechanisms and indicate a potential value of WYE-132 in ovarian cancer treatment.
BackgroundS100P, a protein originally detected in the human placenta, has been found to play an important role in the development and invasion of tumors. Interestingly, we have recently discovered using data mining that S100P was considerably up-regulated during the window of implantation in the human endometrium, but little further information has been available.MethodsReal-time PCR and immunofluorescence were performed to examine the expression and location of S100P in the human endometrium and endometrial cells. Estrogen and progesterone were added to the cultured cells to test the response of S100P to sex steroids.ResultsA dramatic peak, approximately a 100-fold increase in comparison with the proliferative and early- and late-secretory phases, was observed in the endometrium during the mid-secretory phase, which corresponds to the time of embryo implantation. Progesterone regulated the expression of S100P in both primary endometrial epithelial and stromal cells, but estrogen had no significant effect.ConclusionsThe results indicate that S100P participates in the periodic change of the endometrium under the regulation of progesterone, may be used as a unique biomarker of the receptive endometrium and play an important role in embryo implantation.
Study Objective: To investigate whether the number of removed lymph nodes (RLNs) influences the clinical outcome of stage IB1 cervical cancer on the premise of uniform pelvic lymphadenectomy. Design: Retrospective cohort study.
Objective: This study aimed to explore valuable preconception predictors of gestational diabetes mellitus (GDM) in PCOS patients. Methods: A prospective cohort study enrolling infertile Chinese PCOS women treated with ovulation induction was performed. The endocrine, metabolic and physical features of all the patients were collected before pregnancy and then followed up to 6 weeks after delivery. The prevalence of GDM was determined during 24-28 gestational weeks. Logistic regression analysis and receiver operating characteristic (ROC) curves were applied to explore the risk factors and their predictive value for GDM. Results: A total of 94 infertile PCOS women who got singleton pregnancy by ovulation induction were enrolled in the study. Logistic regression analysis showed that the preconception insulin under the curve (IAUC) and sex hormone-binding globulin (SHBG) levels were two most significant risk factors for developing GDM (p ¼ 0.014; p ¼ 0.042, respectively). The area of SHBG and IAUC under the ROC curve were 0.806 (p50.001) and 0.775 (p ¼ 0.001), respectively. The optimal cutoff values were failed to be calculated because of the limited group size. Conclusions: Low SHBG level and hyperinsulinism were both strongly associated with the development of GDM and might be two valuable predictors in PCOS patients.
To explore preconception risk factors for preeclampsia (PE) in women with polycystic ovary syndrome (PCOS), a prospective cohort study was conducted in 92 infertile Chinese women with PCOS who had a singleton pregnancy by ovulation induction and were followed up for 6 weeks after delivery. The patients underwent assessment of physical, endocrine, and metabolic features before ovulation induction. Fifteen (16.3%) patients were diagnosed with PE. Logistic regression analysis showed that preconception sex hormone–binding globulin (SHBG), insulin level at 120 minutes, and body mass index were three independent risk factors for PE (odds ratio [OR], 0.981; 95% confidence interval [CI], 0.964–0.998 [P=.027]; OR, 1.011; 95% CI, 1.000–1.021 [P=.048]; and OR, 1.249; 95% CI, 0.992–1.572 [P=.059], respectively). Receiver operator characteristic analysis indicated the risk value of prepregnancy SHBG, insulin level at 120 minutes, and body mass index (area under the curve=.788, .686, and .697, respectively). Preconception low SHBG levels, overweight/obesity, and hyperinsulinism might be correlated with the subsequent development of PE in patients with PCOS.
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