This PhD work focuses on the effect of elevated glucose levels on the response of prostate cancer cell lines to chemotherapy. Then secondly it concentrates on evaluating the potential for modulating the effect. Clinically relevant prostate cancer is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle; primarily diabetes, characterised by hyperinsulinemia and hyperglycaemia. Insulin-like growth factors and their binding proteins are important mediators of the effects of nutrition on growth and play a key role in the development of prostate cancer. I found that high glucose reduced Docetaxel-induced apoptosis in DU145 and LNCaP cells and that this was mediated by up-regulation of IGFBP-2. Glucose increased IGFBP-2 via increasing the acetylation of histones associated with the IGFBP-2 gene promoter. Next I studied metformin, which is a widely used anti-diabetic drug. The effect of metformin on induction of cell death was much greater in normal glucose conditions but co-treatment with metformin negated the high glucose-mediated reduction in sensitivity to Docetaxel. LKB 1 is required for activation of AMPK in CaP cells but was not essential to mediate induction of cell death in the model. A possible alternative pathway via which metformin exerts its action is through down-regulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:665149 |
| Date | January 2014 |
| Creators | Biernacka, Kalina |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0766 seconds