Differential Utilization of Dietary Fatty Acids in Benign and Malignant Cells of the Prostate

Abstract

Tumor cells adapt via metabolic reprogramming to meet elevated energy demands due to continuous proliferation, for example by switching to alternative energy sources. Nutrients such as glucose, fatty acids, ketone bodies and amino acids may be utilized as preferred substrates to fulfill increased energy requirements. In this study we investigated the metabolic characteristics of benign and cancer cells of the prostate with respect to their utilization of medium chain (MCTs) and long chain triglycerides (LCTs) under standard and glucose-starved culture conditions by assessing cell viability, glycolytic activity, mitochondrial respiration, the expression of genes encoding key metabolic enzymes as well as mitochondrial mass and mtDNA content. We report that BE prostate cells (RWPE-1) have a higher competence to utilize fatty acids as energy source than PCa cells (LNCaP, ABL, PC3) as shown not only by increased cell viability upon fatty acid supplementation but also by an increased ß-oxidation of fatty acids, although the base-line respiration was 2-fold higher in prostate cancer cells. Moreover, BE RWPE-1 cells were found to compensate for glucose starvation in the presence of fatty acids. Of notice, these findings were confirmed in vivo by showing that PCa tissue has a lower capacity in oxidizing fatty acids than benign prostate. Collectively, these metabolic differences between benign and prostate cancer cells and especially their differential utilization of fatty acids could be exploited to establish novel diagnostic and therapeutic strategies.

Regulation of Ketone Body Metabolism and the Role of PPARα

“…In breast and prostate carcinomas, expression of ketolytic enzymes is even regarded as a prognostic marker that is associated with aggressive phenotypes [177,178]. However, some studies indicate that despite the presence of ketolytic enzymes, the ability of ketone body utilization is lost during progression of malignant transformation [179]. Benign epithelial prostate cells are capable of fatty acid β-oxidation and can be rescued by bHB addition during glucose starvation, whereas the more aggressive cells lose metabolic plasticity and cannot switch to bHB metabolism [179].…”

“…However, some studies indicate that despite the presence of ketolytic enzymes, the ability of ketone body utilization is lost during progression of malignant transformation [179]. Benign epithelial prostate cells are capable of fatty acid β-oxidation and can be rescued by bHB addition during glucose starvation, whereas the more aggressive cells lose metabolic plasticity and cannot switch to bHB metabolism [179]. A very special situation has been described in case of hepatocellular carcinoma cells, which reexpress the ketolytic enzyme SCOT during serum starvation [180].…”

Genetics in the Prostate Cancer

“…The Warburg effect is the first defined energy metabolism of cancer cells energy [72]. However, in prostate cancer that is not the matter, as prostate cancer cells do not have increased glucose uptake except advanced stage disease [73].…”

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

“…Only limited data on TCA cycle and OXPHOS activity in primary PCa tissue is available and little is known about specific malignant PCa metabolism 13 . Understanding the impact of mtDNA mutations might help to characterize metabolic adaptations exploited to drive PCa formation and progression.…”