Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids

Abstract

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.

The Integration of Metabolomics with Other Omics: Insights into Understanding Prostate Cancer

“…The metabolism of healthy prostate epithelial cells and acinar epithelial cells are regulated by glycolysis [293,294]. In normal prostate, pyruvate in cytosol enters the mitochondria to be converted into acetyl-coA.…”

“…Under anaerobic conditions, glycolysis is favored, and very little pyruvate is presented to the aerobic mitochondria [267,294]. Regardless of oxygen availability, PCa cells favor glycolysis [114,267,271,294].…”

“…Under anaerobic conditions, glycolysis is favored, and very little pyruvate is presented to the aerobic mitochondria [267,294]. Regardless of oxygen availability, PCa cells favor glycolysis [114,267,271,294]. The Warburg effect was initially associated with dysfunction in mitochondria but is now associated with the cell's quick consumption of glucose, even for those pathways that are outside of mitochondria [302].…”

“…The two-prong role of glutamine in sustaining lipogenesis and glutaminolysis in PCa is highlighted in studies where both glutamine and the glutaminase transporter are overexpressed in tumor cells [397][398][399]. Whereas citrate is generated from OXPHOS via the TCA cycle, the same citrate is produced from α-ketoglutarate via the reverse TCA cycle (reductive carboxylation) [294,400]. This process supports the pathogenesis of PCa and hypoxia-inducible factor 1 (HIF-1) regulatory pathway because the glucose is rechanneled to the acetyl-coA pathway by the influx of glutamine [294].…”

Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer

“…Studies have shown that cellular metabolic reprogramming occurs during the development of prostate cancer and that triterpenoids can intervene in multiple metabolism pathways of prostate cancer cells. 17 It has been reported that UA alters the glycolysis of breast cancer cells with different phenotypes. 18 However, there are few studies on the metabolic, epigenome,…”