ABSTRACT
Naringin is a promising anticancer bioflavonoid phytochemical, mainly extracted from citrus fruits. This study evaluates the antiproliferative effect and the cell death mechanism induced by naringin on cervical cancer (CC) cells. Our results demonstrated that naringin exerts significant inhibition in cell viability and exhibits IC50 value 745, 764, 793 µM against C33A, SiHa, and HeLa cells respectively. Annexin V FITC and immunoblotting analysis reveal significant apoptosis induction in cells exposed to higher doses naringin. Mechanistically, naringin induces endoplasmic reticulum (ER) stress-associated cell killing in CC cells. Naringin increases the protein expression of ER stress sensors, phosphorylates eIF2α by and activates apoptosis-associated protein CHOP and other associated proapoptotic proteins (PARP1 and caspase-3). Intriguingly, pre-treatment with of ER stress inhibitor (salubrinal), reverses the apoptotic effect exerted by naringin. Additionally, the naringin abrogates the ß-catenin pathway by decreasing the protein expression as well as phosphorylation of ß-catenin (Ser576) and GSK-3ß (Ser9) and simultaneously triggers cell cycle arrest at a G0/G1 phase by increasing the expression of cell cycle checkpoint proteins p21/cip and p27/kip. Naringin induces ER stress-mediated apoptosis and simultaneously abrogates Wnt/ß-catenin signaling which eventually triggers the arrest of the cell cycle at a G0/G1 phase in CC cells.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Drugs, Chinese Herbal/pharmacology , Endoplasmic Reticulum Stress/drug effects , Flavanones/pharmacology , G1 Phase Cell Cycle Checkpoints/drug effects , Uterine Cervical Neoplasms/drug therapy , Wnt Signaling Pathway/drug effects , beta Catenin/antagonists & inhibitors , Cell Survival/drug effects , Female , HeLa Cells , Humans , Phosphorylation/drug effects , Polypodiaceae/chemistry , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , beta Catenin/metabolismABSTRACT
We planned to investigate the possible influences of long non-coding RNA (opioid growth factor receptor pseudogene 1) OGFRP1 in endometrial cancer and its potential regulatory mechanism. We measured the level of OGFRP1 in endometrial cancer tissues and evaluated the influences of OGFRP1 dysregulation on the tumour cell biological processes of endometrial cancer cells. Further, the regulatory relationships between OGFRP1 and miR-124-3p, between miR-124-3p and Sirtuin1 (SIRT1) were, respectively, investigated. The interaction between OGFRP1 dysregulation and activation of PI3K/AKT/GSK-3ß pathway was revealed by Western blotting. OGFRP1 was up-regulated in endometrial cancer tissues and cells. OGFRP1 suppression inhibited the malignant behaviour (inhibited cell viability, promoted cell apoptosis, and suppressed cell migration and invasion) of the Ishikawa cells via negatively regulating miR-124-3p. SIRT1 was a target gene of miR-124-3p, and miR-124-3p regulated tumour growth and metastasis by the down-stream signal of SIRT1. Moreover, suppression of OGFRP1 restrained the activation of PI3K/AKT/GSK-3ß signals in the Ishikawa cells via miR-124-3p/SIRT1 axis. Our experiments revealed that upregulation of OGFRP1 may enhance the progression of endometrial cancer by regulating miR-124-3p/SIRT1 axis and by activating PI3K/AKT/GSK-3ß pathway. OGFRP1 may be of significance in illustrating the biology of endometrial cancer.
Subject(s)
Endometrial Neoplasms/genetics , Glycogen Synthase Kinase 3 beta/metabolism , MicroRNAs/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/genetics , Sirtuin 1/genetics , Adult , Aged , Cell Line, Tumor , Cell Proliferation/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Neoplasm Metastasis , Signal Transduction/genetics , Up-RegulationABSTRACT
Lymphadenectomy is critical in the clinical prognosis of ovarian cancer patients. Therefore, we assessed whether lymph node ratio (LNR) has predictive value on overall survival (OS) of patients with serous epithelial ovarian cancer (SEOC). A total of 7,815 eligible SEOC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database, who underwent surgical resection between 1973 and 2013. We used the time-dependent receiver operating characteristic (ROC) curve and the area under curve to determine the optimal cut-off value of LNR. The predictive role of LNR was analyzed by Cox proportional hazards regression model. The effects of LNR and positive lymph nodes (PLN) on OS were evaluated by comparing the time-dependent ROC curves. The time-dependent ROC curves showed that the optimal LNR cut-off value was 42.0% for nodal-positive SEOC. As shown in Kaplan-Meier survival curves, survival was significantly poorer for all patients with LNR≥42.0% (log-rank test: P<0.0001), regardless of the stage. In the multivariate Cox analysis, LNR≥42.0% remained a significant and independent predictor of mortality risk for all patients [hazards ratio: 1.526, 95% confidence interval: 1.415-1.647; P<0.0001], compared with those LNR<42.0%. These results suggest that LNR, rather than the number of PLN or stage, could be regarded as a promising predictor of mortality risk, particularly in stage-III SEOC patients.