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

Abstract

Prostate cancer depends on fatty acid uptake and remodeling of the prostate lipidome, and blocking fatty acid uptake impairs prostate tumorigenesis. Leave the fat out Prostate cancer is one of the most common tumors in men. Although characterized by slow growth rate, preventing prostate cancer progression to an aggressive stage is a major challenge. Watt et al. focused on cancer metabolism and showed increased fatty acid uptake in human malignant prostate cancer tissue. The increased uptake was mediated by up-regulation of the fatty acid translocase CD36. Silencing CD36 in human prostate cancer cells reduced fatty acid uptake and cell proliferation. In prostate cancer mouse and human preclinical models, Cd36 ablation or inhibition reduced prostate cancer severity. The data suggest that CD36 might be targeted for treating prostate cancer. 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.