Abstract
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the major n-3 polyunsaturated fatty acids (PUFAs) in fish oil that decrease the risk of prostate cancer. Tumor-associated macrophages (TAMs) are the main leukocytes of intratumoral infiltration, and increased TAMs correlates with poor prostate cancer prognosis. However, the mechanism of n-3 PUFAs on prostate cancer cell progression induced by TAMs is not well understood. In this study, we investigated the effects of EPA and DHA on modulating of migration and invasion of prostate cancer cells induced by TAMs-like M2-type macrophages. PC-3 prostate cancer cells were pretreated with EPA, DHA, or the peroxisome proliferator-activated receptor (PPAR)-γ antagonist, GW9662, before exposure to conditioned medium (CM). CM was derived from M2-polarized THP-1 macrophages. The migratory and invasive abilities of PC-3 cells were evaluated using a coculture system of M2-type macrophages and PC-3 cells. EPA/DHA administration decreased migration and invasion of PC-3 cells. The PPAR-γ DNA-binding activity and cytosolic inhibitory factor κBα (IκBα) protein expression increased while the nuclear factor (NF)-κB p65 transcriptional activity and nuclear NF-κB p65 protein level decreased in PC-3 cells incubated with CM in the presence of EPA/DHA. Further, EPA/DHA downregulated mRNA expressions of matrix metalloproteinase-9, cyclooxygenase-2, vascular endothelial growth factor, and macrophage colony-stimulating factor. Pretreatment with GW9662 abolished the favorable effects of EPA/DHA on PC-3 cells. These results indicate that EPA/DHA administration reduced migration, invasion and macrophage chemotaxis of PC-3 cells induced by TAM-like M2-type macrophages, which may partly be explained by activation of PPAR-γ and decreased NF-κB p65 transcriptional activity.
Highlights
Prostate cancer is the most common cancer diagnosed among men in developed countries and is the leading cause of cancer deaths worldwide [1]
We found that conditioned medium (CM) from the phorbol 12-myristate 13-acetate (PMA) and M2 groups had significantly lower tumor necrosis factor (TNF)-a, IL-1b, and IL-6 levels than the M1 group
We investigated the potential mechanisms of n-3 polyunsaturated fatty acids (PUFAs) in modulating of PC-3 cells cultured with CM from M2-type macrophages
Summary
Prostate cancer is the most common cancer diagnosed among men in developed countries and is the leading cause of cancer deaths worldwide [1]. Despite improvements in various therapeutic approaches in recent years, therapy for patients with advanced prostate cancer still lacks efficacy. The solid tumor is composed of neoplastic cells and stromal components including fibroblasts, endothelial cells, and migratory hematopoietic cells. TAMs were shown to play crucial roles in survival, proliferation, and metastasis of cancer cells, and higher TAMs infiltration is often correlated with a poor prognosis in many tumors, such as prostate cancer. A clinical study performed by Lissbrant et al [5] found positive correlations of the density of TAMs with prostate tumor cell proliferation and microvessel density. TAMs can facilitate cancer cell migration and invasion by secreting factors, such as growth factors, cytokines, chemotactic factors, and matrix metalloproteinases (MMPs) [6,7,8,9]
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