Gene interactions and pathways from curated databases and text-mining
Toxicol Appl Pharmacol 2004, PMID: 15050414

4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells.

Gao, Ning; Nester, Rebecca A; Sarkar, Mohamadi A

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1alpha and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1alpha and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1alpha and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1alpha and VEGF-A expression. These results suggest that the PI3K/Akt/FRAP signaling pathway is required for HIF-1alpha and VEGF-A expression induced by 4-OHE2, whereas the MAPK pathway is not required. The finding that induction of HIF-1alpha and VEGF-A expression occurs via the activation of the PI3K/Akt/FRAP signaling pathway could be an important mechanism of 4-OHE2-induced carcinogenesis.

Diseases/Pathways annotated by Medline MESH: Ovarian Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

VEGF-A → HIF-1alpha: " In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression "

VEGF-A → mitogen activated protein kinase: " To explore the mechanism of 4-OHE2 induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen activated protein kinase ( MAPK ) signaling pathways are involved in 4-OHE2 induced HIF-1alpha and VEGF-A expression "

VEGF-A → phosphatidylinositol 3-kinase (PI3K): " To explore the mechanism of 4-OHE2 induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen activated protein kinase ( MAPK ) signaling pathways are involved in 4-OHE2 induced HIF-1alpha and VEGF-A expression "

HIF-1alpha → MAPK: " To explore the mechanism of 4-OHE2 induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen activated protein kinase ( MAPK ) signaling pathways are involved in 4-OHE2 induced HIF-1alpha and VEGF-A expression "

HIF-1alpha → phosphatidylinositol 3-kinase (PI3K): " To explore the mechanism of 4-OHE2 induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen activated protein kinase ( MAPK ) signaling pathways are involved in 4-OHE2 induced HIF-1alpha and VEGF-A expression "

VEGF-A → mTOR/FRAP: " Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2 induced HIF-1alpha and VEGF-A expression "

HIF-1alpha → mTOR/FRAP: " Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2 induced HIF-1alpha and VEGF-A expression "

Manually curated Databases

No curated data.