Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer

Abstract

Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

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

“…3B and S3A,B). Recent studies showed that prostate cancer cells show elevated uptake of extracellular fatty acids 4,32 . Our analyses suggest that free fatty acids generated by lipolysis via LIPF can be a potential source of extracellular free fatty acids.…”

“…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 membranes 69,71 . Although exogeneous fatty acid uptake has been shown to be important for prostate cancer 4,32 , the relative importance of exogeneous saturated vs. unsaturated fatty acids has not been examined 32 . Our model predicts that malignant cells will be more sensitive to depletion of exogeneous unsaturated fatty acids due to defective endogenous desaturation.…”

Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

“…Indeed, palmitate-induced metastasis of gastric cancer is dependent on CD36, and high CD36 expression levels in gastric cancer patients correlate with poor clinical outcome; therefore, there is a possibility that blocking of the CD36-palmitate axis may serve as a potential gastric cancer treatment [83]. Indeed, CD36 deletion in a prostate cancer animal model revealed a dramatic decrease in fatty acid uptake and ameliorated cancer progression [86]. Immune cells play pivotal roles in regulating tumor progression.…”

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

“…showed promising preclinical efficacy against PCa, unfavourable drug solubility and pharmacokinetics profiles, off-target effects and side effects including weight loss have hindered clinical development of this agent class (14). 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).…”