Estrogen and progestin regulate HIF-1alpha expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway.
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-1alpha), 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 17beta-estradiol, 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-1alpha was measured by Western blotting. We observed the effect of hormone on nm23-H1 expression after the cells were transfected by siRNA targeting HIF-1alpha or treated with CoCl2 to induce HIF-1alpha overexpression. The 17beta-estradiol increased HIF-1alpha 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 17beta-estradiol (P<0.05), whereas MPA had the opposite effect. The effect was attenuated by HIF-1alpha siRNA (P<0.05) and enhanced by HIF-1alpha overexpression after CoCl2 treatment (P<0.05). Our data suggest that estrogen and progestin regulate HIF-1alpha expression via Akt signaling pathway, affecting nm23-H1 expression in influencing cell metastasis.
Hua
Keqin
K
Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, PR China. huakeqin@126.com
Din
Jingxin
J
Cao
Qi
Q
Feng
Weiwei
W
Zhang
Ying
Y
Yao
Liangqin
L
Huang
Yan
Y
Zhao
Yuqin
Y
Feng
Youji
Y
D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000502:physiology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D054778:NM23 Nucleoside Diphosphate Kinases / Q000032:analysis; D010051:Ovarian Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D002867:Chromones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D054778:NM23 Nucleoside Diphosphate Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; D051057:Proto-Oncogene Proteins c-akt; C517938:NME1 protein, human