Hypoxia negates hyperglycaemia-induced chemo-resistance in breast cancer cells: the role of insulin-like growth factor binding protein 2
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Athba Al Qahtani1, Jeff Holly1 and Claire Perks1
1IGFs and Metabolic Endocrinology Group, School of Clinical Sciences, University of Bristol, Learning and Research Building, Southmead Hospital, Bristol BS10 1TD, UK
Claire Perks, email: [email protected]
Keywords: hyperglycaemia, hypoxia, estrogen receptor, insulin-like growth factor binding protein 2, chemo-resistance
Abbreviations: CoCl2, cobalt chloride; ERα, estrogen receptor α; FASN, fatty acid synthase; HIF-I, hypoxia-inducible factor-I; IGFBP-2, insulin-like growth factor binding protein-2
Received: May 05, 2017 Accepted: July 25, 2017 Published: August 16, 2017
Background: Women who suffer from breast cancer and type II diabetes with associated hyperglycaemia respond less well to chemotherapy. We have shown that hyperglycaemia induces resistance to chemotherapy through upregulation of fatty acid synthase (FASN) in breast cancer cells and increased insulin-like binding protein 2 (IGFBP-2) in prostate cancer cells. As a tumour develops the tumour mass can outgrow the blood supply resulting in the cancer cells being exposed to hypoxia that stimulates many tumorigenic signalling pathways.
Methods: We used MCF-7 and T47D breast cancer cell lines. Trypan blue dye exclusion assay was employed to assess cell death and Western immunoblotting was used to determine changes in protein abundance. Hypoxia was induced both chemically by the addition of cobalt chloride (CoCl2) and using a hypoxia chamber.
Results: IGFBP-2 abundance increased with increasing concentrations of glucose (0-25 mM) that contributed to hyperglycaemia-induced chemo-resistance as it was abrogated by downregulating IGFBP-2 using siRNA. Production of IGFBP-2 is ER dependent: pre-treatment of MCF-7 cells with β-estradiol increased IGFBP-2 and induced chemo-resistance to doxorubicin. The hyperglycaemia-induced chemo-resistance and increases in FASN and IGFBP-2 were negated in a hypoxic environment, with levels of cell death unaffected by glucose concentrations.
Conclusions: The sensitivity of breast cancer cells to chemotherapy is reduced in hyperglycaemic conditions but this effect is negated by hypoxia. These effects appear to be mediated via regulation of IGFBP-2 and FASN. Understanding the role of FASN and IGFBP-2 in chemo-resistance could provide a novel target for improving the effectiveness of breast cancer treatment.
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