Using a natural β-carboline dimer compound to target metabolic vulnerabilities linked to glycolysis in prostate cancer

Overview

Prostate cancer is an androgen dependent cancer and treatments are aimed at preventing activation of the androgen receptor. Part of the development of resistance to therapies involves prostate cancers reprogramming their metabolism to overcome metabolic stress induced by these therapies and support growth and survival. This reprogramming involves increases in the rate of glycolysis and intermediate pathways branching from glycolysis. Previously in our laboratory, the natural compound, beta-carboline dimer, BD, was identified to have potent effects on cell viability, cell cycle, and metabolism in a subset of PCa cells, particularly modulating glucose metabolism.

This project aims to evaluate and validate the observed effects of BD on the glycolysis pathway. Given the selective toxicity of the BD compound, it is anticipated these results could expose the molecular vulnerability underpinning differences in BD sensitivity across our prostate cancer subtypes. BD effect on lactate efflux will be examined by directly measuring intracellular lactate content and efflux using direct lactate measurement (colorimetric assay) and flux technology using the Seahorse platform. BD effects on lactate efflux will be further determined by examining the additional or independent effects on inhibitors targeting different parts of the pathway and measuring lactate production and metabolic response. These data will be evaluated to determine the effect of BD on glycolysis and branchpoint biosynthetic pathways.

Approaches/Skills and Techniques

These experiments will see you become familiar with prostate cancer cell and organoid cultures. Techniques include cell culture, biochemical assays, RNA analysis (including bioinformatic analysis of existing RNAseq data), protein analysis (eg Western blot), metabolic analyses including bioenergetic flux assays.

Outcomes

The overarching aim of this research is to identify novel strategies to target adaptive changes to cancer metabolism. BD is selectively toxic in a subset of cancer cells. The mechanism of action (MOA) and function of BD as it relates to metabolic reprogramming underlying treatment resistance in PCa has not been fully characterised. Therefore, these studies aim to define the effect of BD on glycolysis using in vitro and in vivo models of advanced PCa.

Required skills and experience

Biochemistry, cell and molecular biology, some skills in tissue culture would be desirable but not necessary.

Keywords

• cancer
• prostate cancer
• cancer metabolism
• biochemistry
• cell biology
• drug discovery
• glycolysis
• Warburg effect
• drug resistance

Contact

Please contact Dr Jennifer Gunter for more information (07 3443 7337).