Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

Cathepsins have long been considered as housekeeping molecules. However, specific functions have also been attributed to each of these lysosomal proteases. Squamous cell carcinoma antigen (SCCA) 1, widely expressed in various uterine cervical cells, is an endogenous cathepsin (cat) L inhibitor. In this study, we investigated whether the cat L-SCCA 1 lysosomal pathway and autophagy were involved in resveratrol (RSV)-induced cytotoxicity in cervical cancer cells. RSV induced GFP-LC3 aggregation as well as increased the presence of LC3-II and autophagosomes as was revealed by electron microscopy in cervical cancer cells. Prolonged treatment of RSV induced cytosolic translocation of cytochrome c, caspase 3 activation and apoptotic cell death. This apoptotic effect was abrogated by trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane, an inhibitor of cat B and L, but not by pepstatin A, an inhibitor of cat D. As cervical cancer cells express little cat B, we further studied the role of cat L. RSV induced dissipation of the lysosomal membrane permeability (LMP), leakage and increased cytosolic expression and activity of cat L. Inhibition of cat L by small interference RNA (siRNA) protected cells from RSV-induced cytotoxicity. In contrast, inhibition of SCCA 1 by siRNA promoted RSV-induced cytotoxicity. Inhibition of autophagic response by wortmannin (WT) or asparagine (ASP) resulted in decreased early LC3-II formation, reduced LMP, and abolishment of the increase in RSV-induced cell death. In conclusion, we have identified a new cytotoxic mechanism in which the lysosomal enzyme cat L acts as a death signal integrator in cervical cancer cells. Furthermore, SCCA 1 may play an antiapoptotic role through anti-cat L activity.

Hypoxia and acidosis are microenvironmental selection forces during somatic evolution in breast carcinogenesis. The effect of cobalt chloride (CoCl(2))-induced hypoxia on the expression of hypoxia-inducible factor (HIF)-1alpha, glucose transporter 1 (GLUT1), and carbonic anhydrase IX (CAIX) was assessed in breast cancer cells derived from primary sites (HCC1395 and HCC1937) and metastatic sites (MCF-7 and MDA-MB-231) by reverse transcriptase-polymerase chain reaction and immunoblotting. We analyzed these proteins' expression in tissue samples from normal breast tissue, usual ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) using immunohistochemistry. CAIX mRNA was expressed constitutively in MDA-MB-231 cells but not in the other three cell lines. CAIX mRNA expression was increased after CoCl(2)-induced hypoxia in all four breast cancer cell lines. The expression of HIF-1alpha and GLUT1 proteins was increased after CoCl(2)-induced hypoxia in all breast cancer cell lines tested. Hypoxia significantly increased CAIX protein expression in primary cancer cells but not in metastatic ones. HIF-1alpha was not expressed in benign breast tissue, whereas it was significantly expressed in DH, ADH, DCIS, and IDC (p < 0.001). GLUT1 and CAIX were expressed only in DCIS (56.8% and 25.0%) and IDC (44.1% and 30.5%), with higher expression in high grade DCIS than low/intermediate grade DCIS (79.2% vs. 30.0%, p = 0.001 and 37.5% vs. 10.0%, p = 0.036, respectively). High CAIX expression was significantly associated with poor histological grade of IDC (p = 0.005). During breast carcinogenesis, the role of HIF-1alpha changes from response to proliferation to tumor progression. GLUT1 expression (glycolytic phenotype) and CAIX expression (acid-resistant phenotype) may result in a powerful adaptive advantage and represent an aggressive phenotype.

ABSTRACT. Objective. To evaluate the effect of treatment without aspirin in the acute phase of Kawasaki disease (KD) and to determine whether it is necessary to expose children to high-or medium-dose aspirin.Methods. A total of 162 patients who fulfilled the established criteria of acute KD between 1993 and 2003 were included in this retrospective study. All patients were treated with high-dose intravenous immunoglobulin (IVIG; 2 g/kg) as a single infusion without concomitant aspirin treatment. Low-dose aspirin (3-5 mg/kg per day) was subsequently prescribed when fever subsided. Patients who had defervescence within 3 days after the completion of IVIG treatment were classified as the IVIG-responsive group, and those whose fever persisted for >3 days were classified as the IVIG-nonresponsive group. The 162 patients were divided further into 2 groups: those who were treated with IVIG before illness day 5, and those who were treated after illness day 5. We compared the response rate of IVIG therapy, duration of fever, and incidence of coronary artery abnormalities (CAAs) between these groups.Results. A total of 153 patients were classified into the IVIG-responsive group, and 128 (83.66%) of them had defervescence within 24 hours after completion of IVIG therapy. Nine (5.56%) patients were classified into the IVIG nonresponsive group, and all received additional IVIG (2 g/kg) without aspirin. Six (66.67%) had defervescence within 3 days after additional therapy. Patients in the IVIG-nonresponsive group had a significantly higher incidence of CAAs than those in the IVIG-responsive group (25% vs 2.92%). In the group that was treated before illness day 5 (n ‫؍‬ 16), all patients had defervescence within 3 days after IVIG therapy and 13 (81.25%) had defervescence within 24 hours. In the group that was treated after illness day 5 (n ‫؍‬ 146), 137 (93.84%) patients had defervescence within 3 days and 115 (78.77%) had defervescence within 24 hours. One (6.67%) patient in the group that was treated before illness day 5 got a new onset of CAAs, as did 5 (3.85%) in the group that was treated after illness day 5. There was no statistically significant difference in the response rate of IVIG therapy, duration of fever, and incidence of CAAs between these 2 groups. Conclusion.The results of our study indicate that the treatment without aspirin in acute stage of KD had no effect on the response rate of IVIG therapy, duration of fever, or incidence of CAAs when children were treated with high-dose (2 g/kg) IVIG as a single infusion, despite treatment before or after day 5 of illness. We conclude that it seems unnecessary to expose children to high-or medium-dose aspirin therapy in acute KD when the available data show no appreciable benefit in preventing the failure of IVIG therapy, formation of CAAs, or shortening the duration of fever. K awasaki disease (KD) is an acute systemic vasculitis of unknown origin that occurs predominantly in children who are Ͻ5 years old. The most significant complication is coronary arteritis, and an...

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Background: Approximately 8-38% of children with Kawasaki disease (KD) will have persistent or recrudescent fever after initial intravenous immunoglobulin (IVIG) treatment and are at increased risk for development of coronary artery abnormalities. Using genetic markers may be helpful to identify the high-risk group of IVIG-resistant patients for aggressive treatment. The aim of this study was to evaluate the associations between 4 potential polymorphisms in the interleukin (IL)-1 family of genes and initial IVIG treatment failure in KD children. Methods and Results:A total of 156 KD children (136 with and 20 without a response to IVIG treatment) who were treated with high-dose IVIG (2 g/kg) within 10 days of fever onset were recruited. Polymerase chain reaction and Taqman assays were used for genotyping. A significant increase in IVIG resistance risk was observed for IL-1B −511 TT and IL-1B −31 CC genotypes (adjusted odds ratio (AOR) 5.27, 95% confidence interval (CI) 1.69-16.38, P=0.004; AOR 3.95, 95%CI 1.26-12.41, P=0.019, separately). The diplotype TC/TC (at IL-1B −511 and −31) also showed a significantly increased risk of IVIG resistance (AOR 4.32, 95%CI 1.36-13.71, P=0.013). Conclusions:The IL-1B −511 TT and IL-1B −31 CC genotypes or the TC/TC diplotype may be associated with initial IVIG treatment failure in Taiwanese children with KD. (Circ J 2010; 74: 544 - 551)