Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2

Kalina Biernacka, Rajendra Persad, A Bahl, D Gillatt, Jeffrey Holly, Claire Perks

Research output: Contribution to journalArticle (Academic Journal)peer-review

12 Citations (Scopus)
426 Downloads (Pure)

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 via 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 employed to determine abundance of proteins. Insulin-like growth factor binding protein-2(IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualized 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. 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 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.
Original languageEnglish
Pages (from-to)17-30
Number of pages14
JournalEndocrine-Related Cancer
Volume24
Issue number1
Early online date17 Oct 2016
DOIs
Publication statusPublished - 1 Jan 2017

Structured keywords

  • ICEP

Keywords

  • hyperglycaemia
  • metformin
  • chemotherapy
  • prostate cancer
  • Docetaxel

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