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.
References
[1]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69–90.
[2]
Pollard AJ, Currie A, Rosenberger CM, Heale JP, Finlay BB, et al. (2004) Differential post-transcriptional activation of human phagocytes by different Pseudomonas aeruginosa isolates. Cell Microbiol 6: 639–650.
[3]
Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86: 1065–1073.
[4]
Stewart DA, Yang Y, Makowski L, Troester MA (2012) Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages. Mol Cancer Res 10: 727–738.
[5]
Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, et al. (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17: 445–451.
[6]
Allavena P, Sica A, Solinas G, Porta C, Mantovani A (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66: 1–9.
[7]
Colombo MP, Mantovani A (2005) Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion. Cancer Res 65: 9113–9116.
[8]
Hotchkiss KA, Ashton AW, Klein RS, Lenzi ML, Zhu GH, et al. (2003) Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration. Cancer Res 63: 527–533.
[9]
Lin EY, Pollard JW (2007) Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 67: 5064–5066.
[10]
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20: 649–688.
[11]
Rosen ED, Spiegelman BM (2001) PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: 37731–37734.
[12]
Allred CD, Talbert DR, Southard RC, Wang X, Kilgore MW (2008) PPARgamma1 as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29) cells. J Nutr 138: 250–256.
[13]
Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, et al. (2000) Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A 97: 10990–10995.
[14]
Park BH, Lee SB, Stolz DB, Lee YJ, Lee BC (2011) Synergistic interactions between heregulin and peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist in breast cancer cells. J Biol Chem 286: 20087–20099.
[15]
DeCicco KL, Tanaka T, Andreola F, De Luca LM (2004) The effect of thalidomide on non-small cell lung cancer (NSCLC) cell lines: possible involvement in the PPARgamma pathway. Carcinogenesis 25: 1805–1812.
[16]
Augustsson K, Michaud DS, Rimm EB, Leitzmann MF, Stampfer MJ, et al. (2003) A prospective study of intake of fish and marine fatty acids and prostate cancer. Cancer Epidemiol Biomarkers Prev 12: 64–67.
[17]
Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, et al. (1998) Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst 90: 1637–1647.
[18]
Kobayashi M, Sasaki S, Hamada GS, Tsugane S (1999) Serum n-3 fatty acids, fish consumption and cancer mortality in six Japanese populations in Japan and Brazil. Jpn J Cancer Res 90: 914–921.
[19]
Yang YJ, Lee SH, Hong SJ, Chung BC (1999) Comparison of fatty acid profiles in the serum of patients with prostate cancer and benign prostatic hyperplasia. Clin Biochem 32: 405–409.
[20]
Edwards IJ, Sun H, Hu Y, Berquin IM, O'Flaherty JT, et al. (2008) In vivo and in vitro regulation of syndecan 1 in prostate cells by n-3 polyunsaturated fatty acids. J Biol Chem 283: 18441–18449.
[21]
Sun H, Berquin IM, Owens RT, O'Flaherty JT, Edwards IJ (2008) Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res 68: 2912–2919.
[22]
Kim HK, Della-Fera M, Lin J, Baile CA (2006) Docosahexaenoic acid inhibits adipocyte differentiation and induces apoptosis in 3T3-L1 preadipocytes. J Nutr 136: 2965–2969.
[23]
Tjiu JW, Chen JS, Shun CT, Lin SJ, Liao YH, et al. (2009) Tumor-associated macrophage-induced invasion and angiogenesis of human basal cell carcinoma cells by cyclooxygenase-2 induction. J Invest Dermatol 129: 1016–1025.
[24]
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549–555.
[25]
Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42: 717–727.
[26]
Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, et al. (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175: 1197–1205.
[27]
DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, et al. (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16: 91–102.
[28]
Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9: 259–270.
[29]
Sroka IC, Sandoval CP, Chopra H, Gard JM, Pawar SC, et al. (2011) Macrophage-dependent cleavage of the laminin receptor alpha6beta1 in prostate cancer. Mol Cancer Res 9: 1319–1328.
[30]
Mizutani K, Sud S, McGregor NA, Martinovski G, Rice BT, et al. (2009) The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment. Neoplasia 11: 1235–1242.
[31]
Loberg RD, Ying C, Craig M, Yan L, Snyder LA, et al. (2007) CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia 9: 556–562.
[32]
Ide H, Seligson DB, Memarzadeh S, Xin L, Horvath S, et al. (2002) Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression. Proc Natl Acad Sci U S A 99: 14404–14409.
[33]
Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193: 727–740.
[34]
Nagata D, Yoshihiro H, Nakanishi M, Naruyama H, Okada S, et al. (2008) Peroxisome proliferator-activated receptor-gamma and growth inhibition by its ligands in prostate cancer. Cancer Detect Prev 32: 259–266.
Shen D, Deng C, Zhang M (2007) Peroxisome proliferator-activated receptor gamma agonists inhibit the proliferation and invasion of human colon cancer cells. Postgrad Med J 83: 414–419.
[37]
Annicotte JS, Iankova I, Miard S, Fritz V, Sarruf D, et al. (2006) Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer. Mol Cell Biol 26: 7561–7574.
[38]
Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W (1999) IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274: 30353–30356.
[39]
Niederberger E, Geisslinger G (2008) The IKK-NF-kappaB pathway: a source for novel molecular drug targets in pain therapy? FASEB J 22: 3432–3442.
[40]
Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2: 725–734.
[41]
Chen PS, Shih YW, Huang HC, Cheng HW (2011) Diosgenin, a steroidal saponin, inhibits migration and invasion of human prostate cancer PC-3 cells by reducing matrix metalloproteinases expression. PLoS One 6: e20164.
[42]
Li M, Pascual G, Glass CK (2000) Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol Cell Biol 20: 4699–4707.
[43]
Huang F, Wei H, Luo H, Jiang S, Peng J (2011) EPA inhibits the inhibitor of kappaBalpha (IkappaBalpha)/NF-kappaB/muscle RING finger 1 pathway in C2C12 myotubes in a PPARgamma-dependent manner. Br J Nutr 105: 348–356.
[44]
Guyton K, Zingarelli B, Ashton S, Teti G, Tempel G, et al. (2003) Peroxisome proliferator-activated receptor-gamma agonists modulate macrophage activation by gram-negative and gram-positive bacterial stimuli. Shock 20: 56–62.
[45]
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, et al. (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142: 687–698.
[46]
Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ (2001) Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20: 4188–4197.
[47]
Zerbini LF, Wang Y, Cho JY, Libermann TA (2003) Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. Cancer Res 63: 2206–2215.
[48]
Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2: 161–174.
[49]
Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92: 827–839.
[50]
Lichtinghagen R, Musholt PB, Lein M, Romer A, Rudolph B, et al. (2002) Different mRNA and protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 in benign and malignant prostate tissue. Eur Urol 42: 398–406.
[51]
Jinga DC, Blidaru A, Condrea I, Ardeleanu C, Dragomir C, et al. (2006) MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors. J Cell Mol Med 10: 499–510.
[52]
Bocci G, Man S, Green SK, Francia G, Ebos JM, et al. (2004) Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer Res 64: 6616–6625.
[53]
Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14: 6735–6741.
[54]
Lehrer S, Diamond EJ, Mamkine B, Stone NN, Stock RG (2004) Serum interleukin-8 is elevated in men with prostate cancer and bone metastases. Technol Cancer Res Treat 3: 411.
[55]
Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, et al. (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30: 377–386.
[56]
Pruthi RS, Derksen E, Gaston K (2003) Cyclooxygenase-2 as a potential target in the prevention and treatment of genitourinary tumors: a review. J Urol 169: 2352–2359.
[57]
Kobayashi N, Barnard RJ, Henning SM, Elashoff D, Reddy ST, et al. (2006) Effect of altering dietary omega-6/omega-3 fatty acid ratios on prostate cancer membrane composition, cyclooxygenase-2, and prostaglandin E2. Clin Cancer Res 12: 4662–4670.
[58]
Philibert A, Vanier C, Abdelouahab N, Chan HM, Mergler D (2006) Fish intake and serum fatty acid profiles from freshwater fish. Am J Clin Nutr 84: 1299–1307.