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Background: The effect of histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMTIs) on proliferation of endometrial cancer (EC) cells in vitro and in vivo was investigated. Methods: Changes in methylation of the CDH1 promoter in HDACI- and DNMTI-treated HEC-1-B and RL-952 EC cells were detected. Nude mice with xenografted implants of human EC HEC-1-B cells were treated with valproic acid (VPA) and decitabine (DAC) and evaluated for tumor growth, CDH1 and Bcl-2 mRNA levels. Results: DAC, VPA and suberoylanilide hydroxamic acid (SAHA) inhibited proliferation, induced cell cycle arrest and enhanced the apoptotic index in both cell lines, DAC, VPA and SAHA upregulated E-cadherin mRNA and protein levels and downregulated Bcl-2 mRNA levels in vitro. DAC and VPA inhibited tumor growth, upregulated CDH1 mRNA and downregulated Bcl-2 mRNA levels in vivo. Conclusions: A combination of HDACIs and DNMTIs suppresses the growth of EC, which is likely mediated by upregulation of E-cadherin and downregulation of Bcl-2.

Abstract. Endoplasmic reticulum (ER) is an essential site of cellular homeostasis regulation. ER stress (ERS) may induce autophagy in tumor cells that escape from apoptosis. The present study examined the effects and mechanism of ERS on cisplatin (DDP) sensitivity in ovarian carcinoma. SKOV3 tumor cells treated with Saquinavir were subjected to western blot and reverse transcription-quantitative polymerase chain reaction analysis to determine protein and messenger RNA (mRNA) expression levels of mechanistic target of rapamycin (mTOR) and Beclin 1. MTT assay was used to analyze the influence of Saquinavir on DDP resistance in SKOV3 cells. Saquinavir induced glucose-regulated protein 78 expression, which is a marker of ERS. Following treatment with various doses of Saquinavir, the sensitivity of ovarian cancer cells to DDP decreased significantly. Protein and mRNA expression levels of mTOR and Beclin 1 in SKOV3 cells were increased when the cells were exposed to Saquinavir or DDP for 24 h. Moreover, mTOR and Beclin 1 expression levels were highest in the Saquinavir + DDP group (0.684±0.072 and 0.6467±0.0468, respectively). SKOV3 tumor cells were also exposed to the autophagy inhibitor, 3-methyladenine (3-MA), and different concentrations of Saquinavir. Analysis of half maximal inhibitory concentration (IC 50 ) values of DDP after this treatment demonstrated that IC 50 values were significantly decreased compared with Saquinavir alone (P<0.001), suggesting that the sensitivity to DDP was improved in ovarian cancer cells after 3-MA exposure. These findings demonstrated that Saquinavir is able to induce ERS in SKOV3 cells effectively, and ER-induced stress may decrease the sensitivity of DDP in SKOV3 cells. Furthermore, ERS may regulate cell autophagy through the mTOR and Beclin 1 pathways, leading to a reduction in the sensitivity of DDP in SKOV3 cells. ERS in tumor cells and autophagy may be a potential target to improve the therapeutic effect of chemotherapy and reduce drug resistance in tumors.

The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer.

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