Dietary docosahexaenoic acid impairs prostate cancer progression in TRAMP mice in the early stages of disease through modulation of inflammatory microenvironment

Abstract

The polyunsaturated fatty acid docosahexaenoic acid (DHA) has impressive anti-inflammatory and pro-resolution properties but its therapeutic use in PCa requires pre-clinical evidence. Here, the transgenic adenocarcinoma of the mouse prostate (TRAMP) was used as a pre-clinical model to assess the effect of DHA intake on the inflammatory microenvironment and proliferative and survival pathways in early- and late-stage disease. TRAMP mice were fed with standard rodent or DHA-enriched diet (DHA-d) for 4 (early stage) or 10 weeks (late stage). The ventral prostate was evaluated using histopathological, immunohistochemical, and western blotting analysis. Serum samples were collected for TNF-α measurement. Histopathological analysis showed that DHA-d delayed the progression of PCa and the development of in situ and well-differentiated carcinoma at both ages. Dietary DHA reduced cell proliferation and increased apoptosis by inhibiting the Akt pathway in late-stage disease and activating ERK1/2 signaling in early-stage disease. DHA-d down-regulated pyroptosis and up-regulated necroptosis in the late stage. The intake of DHA reduced CD4+ T-cell and M2-like macrophage and increased CD8+ T-cell infiltration only in the late stage. TNF-α systemic level was down-regulated by DHA-d in both periods but the TNF R1 protein level in the prostate diminished only in the late stage. Overall, DHA-d has a protective effect on prostate carcinogenesis of TRAMP mice by stimulating a low inflammatory and anti-tumor feature, reducing the CD4+/CD8+ ratio, and downregulating the M2-like macrophage profile. Such immunomodulatory effects suggest a protective action of dietary DHA in the early stages of PCa.