Akt-mTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome.

BACKGROUND/AIMS: Abnormal apoptosis of granulosa cells (GCs) is thought to involve in the pathogenesis of polycystic ovary syndrome (PCOS); however, the associated cellular and molecular mechanisms remain unclear. METHODS: Primary GCs were obtained from healthy women and women with PCOS. The cell proliferation and apoptosis were analyzed in insulin-stimulated and insulin receptor gene (INSR) siRNA-transfected GCs. The protein expression of Akt-mTOR-S6K1 signal molecules was measured by Western blot. RESULTS: This study showed that 1 nM of insulin significantly stimulated cell proliferation, induced cell apoptosis, and decreased the telomerase activity in GCs from both the healthy women and PCOS patients (p < 0.001), but silencing of INSR expression blocked the effects of insulin. Insulin induced significantly more apoptosis in GCs from PCOS patients than from healthy women (p < 0.01). Insulin significantly increased the ratio of p-Akt/Akt, the expression of mTOR protein, and the ratio of p-S6K1/S6K1 in GCs from normal control than in cells from PCOS patients (p < 0.001). CONCLUSION: Insulin-induced apoptosis of GCs, less activation of Akt-mTOR signaling, and reduction of telomerase activity may be associated with the pathogenesis of PCOS.

p38MAPK family isoform p38α and activating transcription factor 2 are associated with the malignant phenotypes and poor prognosis of patients with ovarian adenocarcinoma.

This study was to identify the biomarkers for the malignancy and poor prognosis in patients with ovarian cancer. The protein expression of p38MAPK family isoform p38α (p38α) and activating transcription factor 2 (ATF2) was measured in 120 ovarian serous adenocarcinomas and 34 normal fallopian tubes using immunohistochemistry. Stable OV-90 cells expressing p38α and ATF2 inhibitor were established using shRNA lentivirus. Cell proliferation, invasion, and migration were analyzed in vitro. Tumor growth and chemosensitivity were investigated in xenograft tumor models. The percentage of positive p38α and ATF2 expression was significantly higher in ovarian serous adenocarcinomas than that in normal fallopian tubes. Positive p38α and ATF2 expression were significantly associated with high clinical stage (III/IV), lymph node metastasis, and shorter overall survival. Silencing of p38α and ATF2 gene expression in OV-90 cells significantly inhibited cell proliferation, migration, and invasion in vitro. OV-90 cells with p38α and ATF2 gene being silenced grew significantly slow and were significantly sensitive to the chemotherapy compared to cells with high p38α and ATF2 expression. p38α and ATF2 expression play a crucial role in the malignant phenotypes of ovarian tumor cells and are a marker for the poor prognosis of patients with ovarian serous adenocarcinomas.