Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Abstract

There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

FSH inhibits ovarian cancer cell apoptosis by up-regulating survivin and down-regulating PDCD6 and DR5

“…In our previous study, we suggested a model of FSH-VEGF stimulation in ovarian cancer (Huang et al 2008). With the results obtained in the current study, we can supplement this model as shown in Feng Y unpublished data 2010).…”

“…The observations that FSH increases the risk of ovarian malignancy and that pregnancies or oral contraceptives protect the ovaries by suppressing FSH secretion led to numerous studies (Brekelmans 2003), including our previous study (Huang et al 2008) that examined the role of FSH in ovarian carcinogenesis. Collectively, these studies demonstrated that FSH stimulates the growth of normal and immortalized ovarian surface epithelium (OSE) and ovarian cancer cell lines in a dose-and time-dependent manner (Feng et al 1996, Zheng et al 2000, Ji et al 2004.…”

“…However, the exact role and mechanism that FSH plays in ovarian cancer development remain unclear. We have recently reported that FSH increases the expression of VEGF through survivin, which is activated by the PI3K/AKT signaling pathway (Huang et al 2008), suggesting a potential molecular mechanism by which FSH controls tumorigenesis. In the present study, we further demonstrated that FSH promotes ovarian cancer proliferation and suppresses cell apoptosis by upregulating survivin and down-regulating the expression of PCDC6 and DR5, which control cell proliferation and apoptosis respectively.…”

“…The EC50 is 17.04 mIU/ml for SKOV-3 cells, and EC50 is !10 mIU/ml for ES-2 cells. As we reported before (Huang et al 2008), the stimulation conditions of 40 mIU/ml FSH produced the most obvious effects; we used this dose to conduct further experiments for evaluating FSH-stimulated effects in SKOV-3 and ES-2 cells.…”

“…Overexpression of survivin has also been associated with increased cancer metastasis and decreased patient survival (Altieri 2003a,b). Our previous studies indicated that FSH increases the expression of VEGF through survivin, which is activated by the PI3K/AKT signaling pathway (Huang et al 2008).…”