Effects of estradiol on VEGF and bFGF by Akt in endometrial cancer cells are mediated through the NF-κB pathway

• DOI: 10.3892/or.2016.4888
• Publication Date: 2016-06-21T12:19:48Z
• Authors: Jieqing Zhang; Honglin Song; Yanqiong Lu; Haiyan Chen; Si Jiang; Li Li
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; Mice, Inbred BALB C; Estradiol; NF-kappa B; Endometrial Neoplasms; 3. Good health; Fibroblast Growth Factors; Mice; 03 medical and health sciences; Receptors, Estrogen; Cell Movement; Cell Line, Tumor; Animals; Humans; Angiogenesis Inducing Agents; Female; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Cell Division; Cell Proliferation; Signal Transduction

Endometrial carcinogenesis may be related to the long-term effects of estradiol with no antagonism. However, how estradiol regulates cell proliferation is unknown. In the present study, through investigating the molecular events involved in estradiol induced angiogenics factors VEGF and bFGF, we found that estradiol induced endometrial cancer cell division, proliferation, migratory and invasive capacity in vitro and upregulated mRNA expression and protein synthesis of VEGF and bFGF. The estradiol-dependent induction of the expression of VEGF and bFGF was blocked by ER inhibitor, AKT inhibitor and NF-κB inhibitor (PDTC) in estrogen receptor positive Ishikawa cells and blocked by AKT inhibitor, NF-κB inhibitor (PDTC) in estrogen receptor negative HEC-1A cells. Moreover, estradiol activation of AKT was also blocked by AKT antagonist. NF-κB activation was restricted by estradiol concentration and time. Estradiol leading to VEGF and bFGF induction was also confirmed by the development of xenograft tumors in vivo. Taken together, our data suggest that estradiol induces the production of angiogenic factors via a mechanism involving AKT-mediated NF-κB activation partly in non-genomic manner without the estrogen receptor.