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.

[1]  H. Adlercreutz,et al.  Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis. , 1997, Cancer research.

[2]  G. Stancel,et al.  Estrogen regulation of c-fos messenger ribonucleic acid. , 1988, Molecular endocrinology.

[3]  S. Hankinson,et al.  Insulin-like growth factor and breast cancer risk: evidence from observational studies. , 2003, Breast disease.

[4]  Devanand S. Manoli,et al.  Estrogen Masculinizes Neural Pathways and Sex-Specific Behaviors , 2009, Cell.

[5]  M. Blankenstein,et al.  Mitogenic stimulation of human breast cancer cells in a growth factor‐defined medium: Synergistic action of insulin and estrogen , 1988, Journal of cellular physiology.

[6]  E. S.,et al.  Levels of insulin-like growth factor (IGF) binding proteins, luteinizing hormone and IGF-I receptors, and steroids in dominant follicles during the first follicular wave in cattle exhibiting regular estrous cycles. , 1996, Endocrinology.

[7]  Kyung-Chul Choi,et al.  Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models. , 2013, Toxicology.

[8]  V. Ferrans,et al.  Focal adhesion kinase-dependent apoptosis of melanoma induced by tyrosine and phenylalanine deficiency. , 1999, Cancer research.

[9]  B. J. Danzo.  The effects of environmental hormones on reproduction , 1998, Cellular and Molecular Life Sciences CMLS.

[10]  C. Mantzoros,et al.  IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. , 2007, Endocrine-related cancer.

[11]  Kyung-Chul Choi,et al.  Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. , 2012, International Journal of Molecular Medicine.

[12]  Y. Luo,et al.  The mechanisms of anticancer agents by genistein and synthetic derivatives of isoflavone. , 2012, Mini reviews in medicinal chemistry.

[13]  M. Shibuya,et al.  Genistein, a specific inhibitor of tyrosine-specific protein kinases. , 1987, The Journal of biological chemistry.

[14]  Kyung-Chul Choi,et al.  Gene Alterations of Ovarian Cancer Cells Expressing Estrogen Receptors by Estrogen and Bisphenol A Using Microarray Analysis , 2011, Laboratory animal research.

[15]  S. Cummings,et al.  Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. , 2007, Endocrine-related cancer.

[16]  Yiwei Li,et al.  p53-independent apoptosis induced by genistein in lung cancer cells. , 1999, Nutrition and cancer.

[17]  J. York,et al.  Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Kyung-Chul Choi,et al.  Cell growth of BG-1 ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromocyclododecane via upregulation of the cyclin D and cyclin-dependent kinase-4 genes. , 2011, Molecular medicine reports.

[19]  J. Jassem,et al.  Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer. , 2009, European journal of cancer.

[20]  H. Leffers,et al.  The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. , 2006, Human reproduction update.

[21]  K. Kerlikowske,et al.  Hormone replacement therapy and endometrial cancer risk: a meta-analysis. , 1995, Obstetrics and gynecology.

[22]  Kyung-A Hwang,et al.  Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models , 2012, Cancer Gene Therapy.

[23]  S. Bao,et al.  The activation of Akt/PKB signaling pathway and cell survival , 2005, Journal of cellular and molecular medicine.

[24]  Kyung-Chul Choi,et al.  Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression. , 2012, Molecular medicine reports.

[25]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[26]  Kyung-Chul Choi,et al.  4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway. , 2013, Toxicology.

[27]  A. Belfiore,et al.  New advances on the functional cross-talk between insulin-like growth factor-I and estrogen signaling in cancer. , 2012, Cellular signalling.

[28]  C. Erler,et al.  Bisphenol a exposure: human risk and health policy. , 2010, Journal of pediatric nursing.

[29]  T. Hei,et al.  Phytoestrogens and Breast Cancer Prevention: Possible Mechanisms of Action , 2008, Environmental health perspectives.

[30]  Kyung-A Hwang,et al.  Synergistic effects of genetically engineered stem cells expressing cytosine deaminase and interferon-β via their tumor tropism to selectively target human hepatocarcinoma cells , 2012, Cancer Gene Therapy.

[31]  H. Friess,et al.  Prevention of Metastatic Pancreatic Cancer Growth in vivo by Induction of Apoptosis with Genistein, a Naturally Occurring Isoflavonoid , 2003, Pancreas.

[32]  Kyung-Chul Choi,et al.  Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse , 2012, Laboratory animal research.

[33]  I. H. Hamelers,et al.  Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. , 2003, Endocrine-related cancer.

[34]  J. Daurès,et al.  Steroids and adrenomedullin growth patterns in human ovarian cancer cells: estrogenic-regulation assay. , 2003, Gynecologic oncology.

[35]  Kyung-Chul Choi,et al.  Diverse animal models to examine potential role(s) and mechanism of endocrine disrupting chemicals on the tumor progression and prevention: Do they have tumorigenic or anti-tumorigenic property? , 2011, Laboratory animal research.

[36]  J E Paciga,et al.  Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. , 2001, Cancer research.

[37]  A. Bilancio,et al.  PI3‐kinase in concert with Src promotes the S‐phase entry of oestradiol‐stimulated MCF‐7 cells , 2001, The EMBO journal.

[38]  M. Ravindranath,et al.  Anticancer therapeutic potential of soy isoflavone, genistein. , 2004, Advances in experimental medicine and biology.

[39]  L. Altucci,et al.  17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. , 1996, Oncogene.

[40]  J. Connelly,et al.  The role of Bisphenol A in shaping the brain, epigenome and behavior , 2011, Hormones and Behavior.

[41]  R. Schiff,et al.  Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. , 2006, Endocrine-related cancer.

[42]  F. May,et al.  Insulin Receptor Substrate-1 Expression Is Regulated by Estrogen in the MCF-7 Human Breast Cancer Cell Line* , 2000, The Journal of Biological Chemistry.

[43]  A. Woodend,et al.  Estrogen‐related Mood Disorders: Reproductive Life Cycle Factors , 2005, ANS. Advances in nursing science.

[44]  S. Franceschi,et al.  Estrogen and ERα: Culprits in cervical cancer? , 2010, Trends in Endocrinology & Metabolism.

[45]  Qing-Shan Li,et al.  Genistein and its synthetic analogs as anticancer agents. , 2012, Anti-cancer agents in medicinal chemistry.

[46]  Kyung-Chul Choi,et al.  Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression. , 2013, International journal of oncology.

[47]  Tae-Hee Kim,et al.  Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors , 2012, Journal of cellular and molecular medicine.

[48]  Myung-Haing Cho,et al.  Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties. , 2012, Oncology reports.

[49]  Carlos Sonnenschein,et al.  Endocrine disruptors and reproductive health: The case of bisphenol-A , 2006, Molecular and Cellular Endocrinology.

[50]  D. Loo,et al.  In situ detection of apoptosis by the TUNEL assay: an overview of techniques. , 2011, Methods in molecular biology.

[51]  Donald Wlodkowic,et al.  Apoptosis and beyond: cytometry in studies of programmed cell death. , 2011, Methods in cell biology.