Effects of Docosahexaenoic Acid on Prostate Cancer

Abstract

The polyunsaturated fatty acids of the omega-3 class have been widely investigated due to their antitumor properties, including in prostate cancer (PCa). Among them is docosahexaenoic acid (DHA, C22:6 ω-3), whose biological activity is higher than other omega-3s, exhibiting a stronger impact on PCa. The specific mechanisms triggered by DHA are blurred by studies that used a blend of omega-3s, delaying the understanding of its biological role, and hence alternative therapeutic approaches. DHA is differentially processed between normal and malignant epithelial PCa cells, which suggests its function as a tumor suppressor. At cell-specific level, it downregulates key pathways in PCa, such as androgen signaling and lipid metabolism, but also changes membrane composition by disrupting phospholipid balance and increasing unsaturation status, arrests the cell cycle, and induces apoptosis and reactive oxygen species (ROS) overproduction. At the tissue level, DHA seems to influence stromal components, such as the inhibition of cancer-associated fibroblast differentiation and resolution of inflammation, which generates a microenvironment favorable to PCa initiation and progression. Considering that such effects are misunderstood and assigned to omega-3s in general, this review aims to discuss the specific effects of DHA on PCa based on in vitro and in vivo evidence.

Keywords: DHA; PUFAs; fish oil; lipids; omega-3; prostate cancer.

Figure 1

Summary of DHA mechanisms. DHA may enter the cells by diffusion or through membrane receptors GPR120/FFAR4, CD36, and Mfsd2a. Once inside the cells, the omega-3 is likely to trigger downstream biological events, affecting many pathways whose outcome depends on the cell type, its molecular context, and DHA concentration. Legend: DHA—docosahexaenoic acid; ROS—Reactive oxygen species; FA—fatty acids; PUFAs—polyunsaturated fatty acids; ω—omega extremity; α—alpha carbon; GPR120—G-protein coupled receptor 120; FFAR4—Free Fatty Acid Receptor 4; Mfsd2a—Major Facilitator Superfamily Domain containing 2a.

Figure 2

DHA’s specific effects on prostate cancer. DHA obtained through diet or supplementation reaches prostate cancer and may act at the tissue level by decreasing cell migration, resolving inflammation, or inhibiting fibroblast activation. At the cell level, the omega-3 suppresses cell growth via different pathways depending on the androgenic background. In AR-positive cells, it leads to AR degradation through the proteasome, which downregulates AREs and SREBPs, affecting lipid metabolism by decreasing FASN, hence lipogenesis. Also, DHA dysregulates mitochondria and induces ROS overproduction, which is closely related to cell death. Increase in DHA uptake is harmful to the cells because the rise in unsaturation status in their membrane sensitizes them to oxidative damage, but also changes membrane properties related to cell signaling, lipid packing, fluidity, and permeability. Legend: DHA—docosahexaenoic acid; AR—androgen receptor; ROS—reactive oxygen species; AREs—androgen-responsive elements; SREBPs—sterol regulatory element-binding proteins; FASN—fatty acid synthase; CAFs—cancer-associated fibroblasts; YAP—transcriptional coactivator Yes-associated protein; P—phosphate.