xct790 and Endometrial-Neoplasms

Two transcriptional factors, peroxisome proliferator-activated receptor-γ (PPARγ) and estrogen-related receptor-α (ERRα), have been reported to be key regulators of cellular energy metabolism. However, the relationship between ERRα and PPARγ in the development of endometrial cancer (EC) is still unclear. The expression levels of PPARγ and ERRα in EC were evaluated by quantitative real-time PCR, western blot, tissue array and immunohistochemistry. A significant negative correlation was identified between PPARγ and ERRα expression in women with EC (ρ=-0.509, P<0.001). Bioinformatics analyses showed that PPARγ and ERRα can activate or inhibit the same genes involved in cell proliferation and apoptosis through a similar ModFit. ERRα activation or PPARγ inhibition could promote proliferation and inhibit apoptosis through the Bcl-2/Caspase3 pathways. Both PPARγ and ERRα can serve as serum tumor markers. Surprisingly, as evaluated by receiver operating characteristic (ROC) curves and a logistic model, a PPARγ/ERRα ratio≤1.86 (area under the ROC curve (AUC)=0.915, Youden index=0.6633, P<0.001) was an independent risk factor for endometrial carcinogenesis (OR=14.847, 95% CI= 1.6-137.748, P=0.018). EC patients with PPARγ(-)/ERRα(+) had the worst overall survival and disease-free survival rates (both P<0.001). Thus, a dynamic imbalance between PPARγ and ERRα leads to endometrial carcinogenesis and predicts the EC prognosis.

Topics: Anilides; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; ERRalpha Estrogen-Related Receptor; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Nitriles; PPAR gamma; Receptors, Estrogen; ROC Curve; Thiazoles

The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo.. HEC-1A and KLE, ERα-negative endometrial cancer cells exhibiting high ERRα expression levels, and HEC-1A cell-derived xenograft model mice were treated with XCT790. Transcriptional activity and cell proliferation were examined using luciferase, WST-8 and colony formation assays, respectively. Cell cycle progression was evaluated using flow cytometry, immunofluorescence cytochemistry and Western blotting. Apoptosis was evaluated using a caspase-3/7 activity assay.. We found that XCT790 significantly inhibited ERRα-induced in vitro transcriptional activity, including that of the vascular endothelial growth factor (VEGF) gene, in a concentration-dependent manner (p < 0.05). We also found that XCT790 suppressed colony formation and cell proliferation in a concentration and time-dependent manner (p < 0.01) without cytotoxicity, and induced apoptosis (p < 0.01). XCT790 was found to cause cell cycle arrest at the mitotic phase. Akt and mTOR phosphorylation was found to be inhibited by XCT790, but PI3K levels were not found to be significantly affected. Combination therapy of XCT790 with paclitaxel elicited a synergistic inhibitory effect. Additionally, we found that XCT790 significantly inhibited in vivo tumor growth and angiogenesis, and induced apoptosis without a reduction in body weight, in xenograft models (p < 0.01).. From our data we conclude that XCT790 has an anti-tumor effect on endometrial cancer cells in vitro and in vivo. As such, it may serve as a novel therapeutic agent for endometrial cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Endometrial Neoplasms; ERRalpha Estrogen-Related Receptor; Estrogen Receptor alpha; Female; Humans; Mice; Mice, Inbred BALB C; Nitriles; Paclitaxel; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Signal Transduction; Thiazoles; TOR Serine-Threonine Kinases; Transcription, Genetic; Tubulin; Xenograft Model Antitumor Assays