IGF-1 and hyperglycaemia-induced FOXA1 and IGFBP-2 affect epithelial to mesenchymal transition in prostate epithelial cells

Abstract

Localized prostate cancer (PCa) is a manageable disease but for most men with metastatic disease, it is often fatal. A western diet has been linked with PCa progression and hyperglycaemia has been associated with the risk of lethal and fatal prostate cancer. Using PCa cell lines, we examined the impact of IGF-I and glucose on markers of epithelial-to-mesenchymal transition (EMT), migration and invasion. We examined the underlying mechanisms using cell lines and tumour tissue samples. IGF-I had differential effects on the process of EMT: inhibiting in normal and promoting in cancer cells, whereas hyperglycamia alone had a stimulatory effect in both. These effects were independent of IGF and in both cases, hyperglycaemia induced an increase IGFBP-2(tumour promoter) and FOXA1. A positive correlation existed between levels of IGFBP-2 and FOXA1 in benign and cancerous prostate tissue samples and in vitro and in vivo data indicated that FOXA1 strongly interacted with the IGFBP-2 gene in normal prostate epithelial cells that was associated with a negative regulation of IGFBP-2, whereas in cancer cells the level of FOXA1 associating with the IGFBP-2 gene was minimal, suggesting loss of this negative regulation. IGF-I and hyperglycaemia-induced FOXA1/IGFBP-2 play important roles in EMT.