Colston KW, Perks CM, Xie SP and Holly JMGrowth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J Mol Endocrinol 20: 157-162
Division of Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK.Journal of Molecular Endocrinology (Impact Factor: 3.08). 02/1998; 20(1):157-62.
The effects of two vitamin D analogues, EB1089 and CB1093, on insulin-like growth factor binding protein (IGFBP) expression have been examined in MCF-7 and Hs578T human breast cancer cell lines. Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. Recombinant human IGFBP-3 inhibited the growth of MCF-7 cells over the concentration range 1-235 ng/ml. Hs578T cells were unresponsive to the mitogenic effects of IGF-1 but growth was inhibited by the two vitamin D analogues. Treatment of Hs578T cells with EB1089 and CB1093 (10 nM) as well as 100 nM 9-cis retinoic acid (9-cis RA) or all-trans retinoic acid (ATRA) was associated with increased accumulation of IGFBP-3 in conditioned medium. Furthermore, cotreatment of Hs578T cells with EB1089 and 9-cis RA led to augmented effects on both inhibition of cell growth and IGFBP-3 accumulation in conditioned medium as assessed by Western ligand blotting and radioimmunoassay. These findings suggest a role for IGFBP-3 in the growth inhibitory effects of vitamin D analogues.
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- "Positive regulators Tumour suppressor p53 Colon cancer cells  Cytokines, ligands and receptors Vitamin D Cervical and prostate cancer cells     Retinoids Ectocervical and breast epithelial cells   TGF-β1 H u m a n fibroblasts   Breast and prostate cancer cells    TNF-α MDA-MB-231 cells  Chemo-therapeutics Anti-oestrogens MCF-7 cells  Paclitaxel Breast and gastric cancer cells   HDAC inhibitors Liver cancer cells  Demethylating agents Breast cancer cells  Topoisomerase II inhibitors Breast, lung, gastric and prostate cancer cells    Environmental Hypoxia Embryonic stem cells  Squamous cancer cells (oesophageal)  Pancreatic cancer cells  Keratinocytes and fibroblasts (normal and transformed)  Brain, colon, lung, breast, cervical osteosarcoma and prostate cancer cells   IR Endothelial cells  Squamous cell carcinoma cells  Negative regulators Tumour suppressor PTEN Gastric cancer cells  DNA methylation IGFBP-3 promoter Hepatocellular carcinoma   Cytokines, ligands and receptors INF-γ Prostate cancer cells  Positive ER expression Breast epithelial cancer cells [17,59,60,131,143] Fig. 1. Comparison of the in vitro pro-survival and growth-promoting actions of IGFBP-3 with its pro-apoptotic mechanisms. "
ABSTRACT: One of the hallmarks in the advancement of cancer cells is an ability to overcome and acquire resistance to adverse conditions. There has been a large amount of cancer research on IGFBP-3 as a pro-apoptotic molecule in vitro. These pro-apoptotic properties, however, do not correlate with several studies linking high IGFBP-3 levels in breast cancer tissue to rapid growth and poor prognosis. Evidence is emerging that IGFBP-3 also exhibits pro-survival and growth-promoting properties in vitro. How IGFBP-3 pivots cell fate to either death or survival, it seems, comes down to a complex interplay between cells’ microenvironments and the presence of cellular IGFBP-3 binding partners and growth factor receptors. The cytoprotective actions of IGFBP-3 are not restricted to cancer but are also observed in other disease states, such as retinopathy and brain ischaemia. Here we review the literature on this paradoxical nature of IGFBP-3, its pro-apoptotic and growth-inhibitory actions versus its cytoprotective and growth-potentiating properties, and discuss the implications of targeting IGFBP-3 for treatment of disease.
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- "0.5 × 103 cells were seeded in 96-well plate with serum-containing medium for 24 hours starvation. Different concentrations of either commercial rhIGFBP-3 (Sigma) or freshly extracted rhIGFBP-3 protein were added to MCF-7 cells on every 72 hours for a total of 9 days and the cells were finally collected for MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay . HT-29 cells were grown in EMEM (Invitrogen) with 2 mM Glutamine, 1% Non Essential Amino acids (NEAA) and 10% heat-inactivated FBS (Hyclone) at 37°C in a humidified atmosphere with 5% CO2. "
ABSTRACT: Insulin-like growth factor binding protein-3 (IGFBP-3) is a multifunctional molecule which is closely related to cell growth, apoptosis, angiogenesis, metabolism and senescence. It combines with insulin-like growth factor-I (IGF-I) to form a complex (IGF-I/IGFBP-3) that can treat growth hormone insensitivity syndrome (GHIS) and reduce insulin requirement in patients with diabetes. IGFBP-3 alone has been shown to have anti-proliferation effect on numerous cancer cells. We reported here an expression method to produce functional recombinant human IGFBP-3 (rhIGFBP-3) in transgenic rice grains. Protein sorting sequences, signal peptide and endoplasmic reticulum retention tetrapeptide (KDEL) were included in constructs for enhancing rhIGFBP-3 expression. Western blot analysis showed that only the constructs with signal peptide were successfully expressed in transgenic rice grains. Both rhIGFBP-3 proteins, with or without KDEL sorting sequence inhibited the growth of MCF-7 human breast cancer cells (65.76 ± 1.72% vs 45.00 ± 0.86%, p < 0.05; 50.84 ± 1.97% vs 45.00 ± 0.86%, p < 0.01 respectively) and HT-29 colon cancer cells (65.14 ±3.84% vs 18.01 ± 13.81%, p < 0.05 and 54.7 ± 9.44% vs 18.01 ± 13.81%, p < 0.05 respectively) when compared with wild type rice. These findings demonstrated the feasibility of producing biological active rhIGFBP-3 in rice using a transgenic approach, which will definitely encourage more research on the therapeutic use of hIGFBP-3 in future.
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- "The ER-α negative cell lines secrete predominantly IGFBP-3 . Furthermore IGFBP-3 is known to mediate the effects of a number of different inhibitors of cell growth and inducers of apoptosis, such as TGF-beta, p53, vitamin D and tamoxifen     . In this study we treated four different breast cancer cell lines with the DNA methytransferase inhibitor, AZA to determine the role played by IGFBP-3 in the effects of AZA on total cell number, cell survival and colony formation. "
ABSTRACT: Breast cancer progression is associated with loss of estrogen receptor(ER-α), often due to epigenetic silencing. IGFBP genes have consistently been identified among the most common to be aberrantly methylated in tumours. To understand the impact of losing IGFBP-3 tumour expression via DNA methylation, we treated four breast cancer cell lines (MCF-7, T47D, Hs578T and MDA-MB-231) with a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine(AZA) to determine IGFBP-3's role in the effects of AZA on total cell number and survival relative to changes in the ER. AZA induced cell growth inhibition, death and a reduction in the formation of colonies, despite increasing ER-α expression in ER-negative cells but reducing ER-α in ER-positive cells. Regardless of the differential effects on the ER-α, AZA consistently increased the abundance of IGFBP-3 and negating this increase in IGFBP-3 with siRNA reduced the AZA-induced growth inhibition and induction of cell death and virtually negated the AZA-induced inhibition of colony formation. With ER-α positive cells AZA increased the abundance of the tumour suppressor gene, p53 and induced demethylation of the IGFBP-3 promoter, whereas with ER negative cells, AZA epigenetically increased the transcription factor AP2-α, which when silenced prevented the increase in IGFBP-3. IGFBP-3 plays an important role in the anti-tumorigenic effects of AZA on breast cancer cells.