The role of metabolism in prostate cancer progression and bone metastases

Prostate cancer (PCa) is the most common cancer in males in the Western world, and whilst treatment of localised disease is very effective, bone metastatic disease remains incurable and overall survival is only around 2-3 years. In view of this there is a need to identify novel therapeutics. Dysregulated cellular energetics is one of the new hallmarks of cancer, however the changes in cancer metabolism that occur when cancer metastasises remain relatively unexplored. The aim of this project was to identify the changes in PCa metabolism when it metastasises to the bone microenvironment, with the hope of identifying novel targets for advanced PCa therapeutics.
Using a combination of in vitro metabolomic profiling of PCa/bone cell co-cultures, an in vivo mouse model of PCa bone disease and in silico analyses of patient data sets it was established that the bone metastatic site causes alterations in several metabolic pathways in PCa cells, including up-regulation of oxidative phosphorylation, the tricarboxylic acid cycle, and the pentose phosphate pathway (PPP). The PPP alterations were of interest as this pathway provides nucleotide precursors necessary for cellular proliferation, and is the main cellular source of NADPH, which is vital in cellular detoxification of potentially harmful free radicals. PPP enzymes were found to be more highly expressed in bone metastatic PCa cell lines compared to benign or non-bone metastatic cell lines, and expression of its rate limiting enzyme glucose-6-phosphate-dehydrogenase (G6PD) could be up-regulated by bone marrow stromal cells (BMSCs), suggesting that the bone microenvironment is driving this effect. In multiple patient data sets G6PD mRNA expression was elevated in metastatic samples, particularly bone metastatic samples, and expression was higher in castration resistant prostate cancer samples compared to hormone dependent. BMSCs were found to secrete high levels of interleukin-6 (IL-6), and blocking IL-6 was able to in part abrogate the up-regulation of G6PD, whilst recombinant IL-6 could induce G6PD up-regulation.
BMSCs increased reactive oxygen species (ROS) in PCa cells and reduced the viability of non-bone metastatic cell lines. This was evident in vitro and in a xenograft mouse model. Pharmacological inhibition of G6PD further increased ROS levels, suggesting PCa up-regulates G6PD to counteract the high ROS induced by BMSCs.
Pharmacological or genetic blockade of G6PD in PCa cells reduced their proliferation, inhibited cell migration, reduced expression of mesenchymal markers, decreased antioxidant levels, increased ROS levels, and increased sensitivity to chemotherapy. Overexpression of G6PD promoted PCa cell proliferation and increased antioxidant levels. In vivo, knockdown of G6PD expression in PCa cells could reduce tumour burden within bone.
This work demonstrates for the first time that stromal cells of the metastatic environment drive changes in the metabolism of cancer cells that can promote their anti-oxidant abilities and increase their resistance to chemotherapy. Pharmacological targeting of the PPP pathway could be a novel approach to improve the efficacy of currently used treatments.

Keywords: Prostate
Metabolism
Bone
Cancer
Advisor: Edwards, CM
Rao, SR
Hamdy, FC