title: Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2.
abstract: Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.
authors: IGFs and Metabolic Endocrinology Group, School of Clinical Sciences at North Bristol, Southmead Hospital, UK.
authors: K M
authors: KM
authors: Biernacka
authors: C C
authors: CC
authors: Uzoh
authors: L
authors: L
authors: Zeng
authors: R A
authors: RA
authors: Persad
authors: A
authors: A
authors: Bahl
authors: D
authors: D
authors: Gillatt
authors: C M
authors: CM
authors: Perks
authors: J M P
authors: JM
authors: Holly
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009284:Naphthols / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D009284:Naphthols; D034741:RNA, Small Interfering; D043823:Taxoids; C439060:sirtinol; D000077143:Docetaxel; C012589:trichostatin A; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2
keywords: IGF; carcinoma; chemotherapy; obesity; prostate