Estrogen and progestin regulate HIF-1α expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway

Abstract

Our previous study revealed that estrogen regulates nm23-H1 expression thus promoting cell migration-invasion via activating PIK3/Akt pathway. In this study, we explored the effect of hormone on hypoxia-inducible factor-1 (HIF-1α), a key factor in cancer invasion and metastasis, via activation of Akt signaling transduction pathway. We treated two ovarian cancer cell lines ES-2 and SKOV3 with 17βestradiol, methoxyprogesterone acetate (MPA) only, or hormone combined with and Akt, MAPK pathway inhibitor, or transefected with siRNA targeting Akt sequenced with hormone. Expression of HIF-1α was measured by Western blotting. We observed the effect of hormone on nm23-H1 expression after the cells were transfected by siRNA targeting HIF-1α or treated with CoCl2 to induce HIF-1α overexpression. The 17β-estradiol increased HIF-1α expression in ovarian cancer cells, and this upregulatory effect was abrogated by Akt inhibitor LY294002 (P<0.05) and Akt siRNA interference (P<0.05), but not affected by MAPK inhibitor PD980059 (P>0.05). MPA had the opposite effect. Nm23-H1 protein expression in ES-2 and SKOV3 cells were decreased after treatment with 17β-estradiol (P<0.05), whereas MPA had the opposite effect. The effect was attenuated by HIF-1α siRNA (P<0.05) and enhanced by HIF-1α overexpression after CoCl2 treatment (P<0.05). Our data suggest that estrogen and progestin regulate HIF-1α expression via Akt signaling pathway, affecting nm23-H1 expression in influencing cell metastasis.