title: Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.
abstract: The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation 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.
authors.affiliation: IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK mdxkz@bristol.ac.uk.
authors.forename: K M
authors.initials: KM
authors.lastname: Biernacka
authors.affiliation: Department of UrologySouthmead Hospital, Bristol, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Persad
authors.affiliation: Department of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK.
authors.forename: A
authors.initials: A
authors.lastname: Bahl
authors.affiliation: Department of UrologySouthmead Hospital, Bristol, UK.
authors.forename: D
authors.initials: D
authors.lastname: Gillatt
authors.affiliation: IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK.
authors.forename: J M P
authors.initials: JM
authors.lastname: Holly
authors.affiliation: IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Perks
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: Docetaxel; chemotherapy; hyperglycaemia; metformin; prostate cancer