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.
Highlights
Prostate cancer (PCa) is the most common non-cutaneous cancer in men, and it accounts for the second highest cause of mortality among men in the US after lung cancer (Siegel et al 2012).The global obesity and associated diabetes epidemics have been linked with an increase in the development and/or progression of a number of cancers
We present data showing that metformin can act in an LKB1-AMPK-independent way to induce prostate cancer cell death and counter hyperglycaemiainduced chemoresistance and that these effects involve the regulation of Insulin-like growth factor-binding protein-2 (IGFBP-2)
With DU145, we found that metformin was able to induce a dose-dependent increase in cell death under euglycaemic conditions compared with hyperglycaemic conditions where cell death was not significantly affected by any dose of metformin
Summary
Prostate cancer (PCa) is the most common non-cutaneous cancer in men, and it accounts for the second highest cause of mortality among men in the US after lung cancer (Siegel et al 2012). The global obesity and associated diabetes epidemics have been linked with an increase in the development and/or progression of a number of cancers. There is currently a lot of interest in metformin, a drug commonly used to treat diabetes mellitus, that became a standard treatment after other members of the biguanides family, phenformin and buformin, which were discontinued due to increased risk of lactic acidosis (Kolata 1979, Bailey & Turner 1996, Witters 2001)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
