ABSTRACT
Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.
Subject(s)
Azepines/pharmacology , Endometrial Neoplasms/drug therapy , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Triazoles/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Female , G1 Phase Cell Cycle Checkpoints/drug effects , G1 Phase Cell Cycle Checkpoints/genetics , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Humans , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , RNA Interference , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Burden/drug effects , Tumor Burden/genetics , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Amplification and overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types. Using ovarian cancer cell lines, a transgenic mouse model, and primary cell cultures from human ovarian cancer tissues, we demonstrated that JQ1 significantly suppressed cellular proliferation and induced cell cycle arrest and apoptosis in ovarian cancer cells and mouse model via targeting c-Myc. In addition, JQ1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors. Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.
Subject(s)
Antineoplastic Agents/chemistry , Azepines/chemistry , Gene Expression Regulation, Neoplastic , L-Lactate Dehydrogenase/biosynthesis , Neoplasms/drug therapy , Triazoles/chemistry , Animals , Apoptosis , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation , Female , Humans , Immunohistochemistry , Isoenzymes/biosynthesis , Lactate Dehydrogenase 5 , Membrane Potential, Mitochondrial , Mice , Necrosis , Neoplasm Metastasis , Oligonucleotide Array Sequence Analysis , Ovarian Neoplasms/drug therapy , Proto-Oncogene Proteins c-myc/metabolism , RNA Interference , Reactive Oxygen Species/metabolism , TranscriptomeABSTRACT
OBJECTIVE: The aim of this study is to report recurrence-free and overall survival for women with endometrial adenocarcinoma who were surgically staged using robotic-assisted laparoscopy. METHODS: A retrospective chart review was performed for all consecutive endometrial adenocarcinoma patients surgically staged with robotic-assisted laparoscopy at the University of North Carolina Hospital from 2005 to 2010. Demographic data, 5-year survival, and recurrence-free intervals were analyzed. Statistical analysis using Chi-square, t-test, and Kaplan-Meier curves were performed with SAS software. Study results were compared to endometrial cancer statistics from the Surveillance Epidemiology and End Results database from the National Cancer Institute. RESULTS: A total of 499 patients were identified and included in the study. Recurrence-free intervals after robotic-assisted surgical staging were 85.2% for stage IA, 80.2% for stage IB, 69.8% for stage II, and 69% for stage III. Projected 5-year survival was 88.7% for all patients included in the study. Nearly 82% of cases were endometrioid adenocarcinoma, with papillary serous, clear cell or mixed histology comprising 17.4% of cases. Median follow up time was 23 months, with a range of 0 to 80 months. Among stage IA, IB, II, and III patients, projected overall survival was 94.2%, 85.9%, 77.4%, and 68.6%, respectively. CONCLUSIONS: The results from this study demonstrate that robotic-assisted surgical staging for endometrial cancer does not adversely affect rates of recurrence or survival. These findings provide further evidence that robotic-assisted laparoscopic surgical staging is not associated with inferior results when compared to laparotomy or traditional laparoscopy.
