Yu Huang

Inhibition of CDK1 by RO-3306 Exhibits Anti-Tumorigenic Effects in Ovarian Cancer Cells and a Transgenic Mouse Model of Ovarian Cancer

Ovarian cancer is the deadliest gynecological malignancy of the reproductive organs in the United States. Cyclin-dependent kinase 1 (CDK1) is an important cell cycle regulatory protein that specifically controls the G2/M phase transition of the cell cycle. RO-3306 is a selective, ATP-competitive, and cell-permeable CDK1 inhibitor that shows potent anti-tumor activity in multiple pre-clinical models. In this study, we investigated the effect of CDK1 expression on the prognosis of patients with ovarian cancer and the anti-tumorigenic effect of RO-3306 in both ovarian cancer cell lines and a genetically engineered mouse model of high-grade serous ovarian cancer (KpB model). In 147 patients with epithelial ovarian cancer, the overexpression of CDK1 was significantly associated with poor prognosis compared with a low expression group. RO-3306 significantly inhibited cellular proliferation, induced apoptosis, caused cellular stress, and reduced cell migration. The treatment of KpB mice with RO-3306 for four weeks showed a significant decrease in tumor weight under obese and lean conditions without obvious side effects. Overall, our results demonstrate that the inhibition of CDK1 activity by RO-3306 effectively reduces cell proliferation and tumor growth, providing biological evidence for future clinical trials of CDK1 inhibitors in ovarian cancer.

Elevated microRNA‐130b‐5p or silenced ELK1 inhibits self‐renewal ability, proliferation, migration, and invasion abilities, and promotes apoptosis of cervical cancer stem cells

AbstractCervical cancer (CC) is the most familiar gynecological malignancy. With the poor prognosis of CC patients, this study explored the effect of microRNA (miR)‐130b‐5p targeting ELK1 expression on self‐renewal ability and stemness of CC stem cells. The tissues of patients with CC or cervical benign lesions were collected. MiR‐130b‐5p and ELK1 expression was detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. Human CC cell line Hela was cultured and the induced CC stem cells were introduced with miR‐130b‐5p mimic or silenced ELK1 to figure their roles in self‐renewal ability, stemness, colony formation, proliferation, migration, invasion abilities, and apoptosis of CC stem cells. Tumor growth was detected in nude mice in vivo. The targeting relationship between miR‐130b‐5p and ELK1 was analyzed using bioinformatic prediction and dual luciferase reporter gene assay. Decreased miR‐130b‐5p and elevated ELK1 existed in CC tissues of patients. Up‐regulated miR‐130b‐5p decreased ELK1 expression in CC stem cells. Elevated miR‐130b‐5p or silenced ELK1 inhibited self‐renewal ability and stemness, colony formation, proliferation, migration and invasion abilities, promoted apoptosis of CC stem cells, as well as decreased the weight and volume of tumor in nude mice. ELK1 was found to be targeted by miR‐130b‐5p. Overexpression ELK1 effectively reversed the cellular phenotypic changes and tumor formation in vivo caused by up‐regulation of miR‐130b‐5p. We conclude that up‐regulated miR‐130b‐5p or silenced ELK1 inhibits CC stem cell growth.