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 hypoxia-inducible factor-1 (HIF-1alpha). Knockdown of survivin or HIF-1alpha 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.

• Authors: Yan Huang, Keqin Hua, Xianrong Zhou, Hongyan Jin, Xiaojun Chen, Xin Lu, Yinhua Yu, Xiliang Zha, Youji Feng
• Journal: Cell research (Cell Res) Vol. 18 Issue 7 Pg. 780-91 (Jul 2008) ISSN: 1748-7838 [Electronic] England
• PMID: 18574502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Survivin
• Vascular Endothelial Growth Factor A
• Follicle Stimulating Hormone
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Adult
• Cell Line, Tumor
• Cystadenocarcinoma, Serous (metabolism)
• Female
• Follicle Stimulating Hormone (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (genetics, metabolism)
• Middle Aged
• Neoplasm Proteins (genetics, metabolism)
• Ovarian Neoplasms (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Signal Transduction
• Survivin
• Vascular Endothelial Growth Factor A (genetics)