Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor α and insulin-like growth factor-1 receptor signaling pathways.
The interaction between estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to estrogen dependent cancers. Estrogen (E2) upregulates the expression of components of IGF-1 system and induces the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). In the present study, we evaluated the xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. BPA was determined to affect this crosstalk by upregulating mRNA expressions of ERα and IGF-1R and inducing phosphorylation of IRS-1 and Akt in protein level in BG-1 ovarian cancer cells as E2 did. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumor burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumor mass compared to vehicle, indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model and also significantly decreased tumor growth and in vivo expressions of ERα, pIRS-1, and pAkt in xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ERα and IGF-1R signaling pathways upregulated by BPA or E2.
Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
Kyung-A
KA
Hwang
Min-Ah
MA
Park
Nam-Hee
NH
Kang
Bo-Rim
BR
Yi
Sang-Hwan
SH
Hyun
Eui-Bae
EB
Jeung
Kyung-Chul
KC
Choi
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001559:Benzhydryl Compounds / Q000633:toxicity*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000502:physiology* / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000098826:Bisphenol A Compounds
D016588:Anticarcinogenic Agents; D001559:Benzhydryl Compounds; D004958:Estradiol; D047628:Estrogen Receptor alpha; D019833:Genistein; D010636:Phenols; D017526:Receptor, IGF Type 1; C006780:bisphenol A; D000098826:Bisphenol A Compounds
BG-1 ovarian cancer cells; Bisphenol A; Genistein; IGF-1R; pAkt; pIRS-1