Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer

Abstract

Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased de novo synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source ($83%) of carbons to the total lipid pool in all cell lines, compared with glucose ($13%) and glutamine ($4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1-mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression.Implications: Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.

Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

“…There is increasing acknowledgement that various lipid scavenging pathways, including transporter-mediated uptake, tunneling nanotubes [46], lipid-conjugated albumin uptake [64] and macropinocytosis [18] are critical supply routes of exogenous lipids fueling bioenergetic processes and biomass production that underpin tumor growth and survival. Recent studies of cancer cells expressing the lipogenic phenotype, including PCa, estimated that >70% of the lipid-derived carbon biomass is derived from uptake and only 30% from synthesis based on carbon tracing of serum-derived free FAs [65, 66]. However, these estimates are limited by the fact that the serum lipidome is highly complex and that >95% of serum FAs are acyl conjugates across all lipid classes, including TAGs, CEs and phospholipids.…”

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…Inactivation of fatty acid desaturation creates the need to uptake exogeneous unsaturated fatty acids in order to maintain correct composition of saturated vs. unsaturated lipids in biological membranes69,71 . Although exogeneous fatty acid uptake has been shown to be important for prostate cancer4, 32 , the relative importance of exogeneous saturated vs. unsaturated fatty acids has not been examined32 . Our model predicts that malignant cells will be more sensitive to depletion of exogeneous unsaturated fatty acids due to defective endogenous desaturation.…”

“…Furthermore, our tumor-specific model also predicts that perturbations in multiple genes of the fatty acid synthesis pathway are selectively lethal in malignant cells ( Table 1). Given that dysregulation of lipid and fatty acid metabolism is a major feature of prostate cancer4, 32 , we further explore spatial heterogeneity of FA and lipid metabolism using spatially-resolved metabolic network models.…”

“…Metabolic genes in lipolysis (LIPF), and fatty acid synthesis (ACSL5) are selectively expressed in the malignant region ( Figure 3B and S3A & B). Recent studies showed that prostate cancer cells show elevated uptake of extracellular fatty acids4, 32 . Our analyses suggest that free fatty acids generated by lipolysis via LIPF can be a potential source of extracellular free fatty acids.…”

DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

“…In addition to de novo synthesis of FAs, PCa cells depend on lipid uptake from the circulation, and from stromal adipocytes (20,41,42). We showed previously that extracellular FAs are the major contributor to lipid synthesis in PCa (22). Moreover, targeting FA uptake using an antibody against CD36, a major transporter for exogenous FAs into the cells, reduced cancer severity in patient-derived xenografts, and CD36 deletion slowed cancer progression in prostate-specific PTEN -/mice.…”