Reprogramming of metabolic pathways is a hallmark of cancer. Cancer cells rewire specific metabolic pathways to meet their high energy and metabolite needs and enhance cellular antioxidant capacity for sustained growth, leading to unique, often tumour-specific metabolic traits that can provide novel therapeutic targets. Our objective is to identify these traits in prostate cancer cells (PCa), explore if they present a metabolic vulnerability which can be therapeutically exploited with repurposed drugs or novel agents from Nature.
During a recent screening campaign of ascidian extracts from the Great Barrier Reef, we isolated the natural compound BD which displayed cytotoxicity in a select group of cancer cell lines. Mechanism of action studies by DNA microarray, Western blotting, and metabolic investigations of fuel flexibility, mitochondrial activity, glucose, lipid and amino acid uptake, lipid content, and antioxidant capacity revealed that BD induces amino stress, exposing BD-treated PCa cells to synergistic inhibition with antagonists of amino acid metabolism. Intriguingly, transcriptional profiling suggested that BD affects serine/glycine biosynthesis and causes cellular depletion of serine, glycine and cysteine. These three amino acids are intricately interlinked in redox homeostasis and the serine/glycine and one-carbon metabolism which fuel the synthesis of purines, proteins, lipids and glutathione. Consistent with this, BD induced reactive oxygen species, decreased mitochondrial activity and glutamine uptake and completely inhibited glutaminolysis. Ongoing work indicates that BD targets a unique metabolic trait expressed by PCa cell lines that are critically dependent on de novo synthesis of serine instead of serine import.