Advertisement

Cancer Immunology, Immunotherapy

, Volume 64, Issue 2, pp 249–258 | Cite as

N-3 polyunsaturated fatty acids inhibit IFN-γ-induced IL-18 binding protein production by prostate cancer cells

  • Xiaofeng Wang
  • Andrew Breeze
  • Marianna KulkaEmail author
Original Article

Abstract

Prostate cancer cells can produce IL-18 binding protein (IL-18BP) in response to interferon-γ (IFN-γ), which may function to neutralize IL-18, an anti-tumor factor formerly known as IFN-γ inducing factor. The consumption of n-3 polyunsaturated fatty acids (PUFAs) has been associated with a lower risk of certain types of cancer including prostate cancer, although the precise mechanisms of this effect are poorly understood. We hypothesized that n-3 PUFAs could modify IL-18BP production by prostate cancer cells by altering IFN-γ receptor-mediated signal transduction. Here, we demonstrate that n-3 PUFA treatment significantly reduced IFN-γ-induced IL-18BP production by DU-145 and PC-3 prostate cancer cells by inhibiting IL-18BP mRNA expression and was associated with a reduction in IFN-γ receptor expression. Furthermore, IFN-γ-induced phosphorylation of Janus kinase 1 (JAK1), signal transducers and activators of transcription 1 (STAT1), extracellular signal-regulated kinases 1/2 (ERK1/2), and P38 were suppressed by n-3 PUFA treatment. By contrast, n-6 PUFA had no effect on IFN-γ receptor expression, but decreased IFN-γ-induced IL-18BP production and IFN-γ stimulation of JAK1, STAT1, ERK1/2, and JNK phosphorylation. These data indicate that both n-3 and n-6 PUFAs may be beneficial in prostate cancer by altering IFN-γ signaling, thus inhibiting IL-18BP production and thereby rendering prostate cancer cells more sensitive to IL-18-mediated immune responses.

Keywords

N-3 PUFAs IFN-γ signaling IL-18 binding protein Prostate cancer cells 

Abbreviations

IFN-γR

Interferon-γ receptor

IL

Interleukin

IL-18BP

IL-18 binding protein

DHA

Docosahexaenoic acid

DPA

Docosapentaenoic acid

ELISA

Enzyme-linked immunosorbent assay

EPA

Eicosapentaenoic acid

ERK

Extracellular signal-regulated kinase

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

GC–MS

Gas chromatography–mass spectrometry

JAK

Janus kinase

JNK

c-Jun N-terminal kinase

MHC

Major histocompatibility complex

NK

Natural killer

PBS

Phosphate-buffered saline

PPARs

Peroxisome proliferator-activated receptors

PUFAs

Polyunsaturated fatty acids

qPCR

Quantitative polymerase chain reaction

SH

Src homology

STAT

Signal transducers and activators of transcription

TBS

Tris-buffered saline

TBST

TBS containing 0.05 % tween-20

Th

T helper

TNF

Tumor necrosis factor

Notes

Acknowledgments

We thank Dr. Adriana Catalli for technical support. This work was supported by The Canadian Institute for Health Research, the National Research Council Canada, and the Canadian Breast Cancer Foundation-Atlantic.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

262_2014_1630_MOESM1_ESM.pdf (307 kb)
Supplementary material 1 (PDF 306 kb)

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917. doi: 10.1002/ijc.25516 PubMedCrossRefGoogle Scholar
  2. 2.
    Quon H, Loblaw A, Nam R (2011) Dramatic increase in prostate cancer cases by 2021. BJU Int 108(11):1734–1738. doi: 10.1111/j.1464-410X.2011.10197.x PubMedCrossRefGoogle Scholar
  3. 3.
    Leung BP, Culshaw S, Gracie JA, Hunter D, Canetti CA, Campbell C, Cunha F, Liew FY, McInnes IB (2001) A role for IL-18 in neutrophil activation. J Immunol 167(5):2879–2886PubMedCrossRefGoogle Scholar
  4. 4.
    Darwich L, Coma G, Pena R, Bellido R, Blanco EJ, Este JA, Borras FE, Clotet B, Ruiz L, Rosell A, Andreo F, Parkhouse RM, Bofill M (2009) Secretion of interferon-gamma by human macrophages demonstrated at the single-cell level after costimulation with interleukin (IL)-12 plus IL-18. Immunology 126(3):386–393. doi: 10.1111/j.1365-2567.2008.02905.x PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Srivastava S, Pelloso D, Feng H, Voiles L, Lewis D, Haskova Z, Whitacre M, Trulli S, Chen YJ, Toso J, Jonak ZL, Chang HC, Robertson MJ (2013) Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin. Cancer Immunol Immunother 62(6):1073–1082. doi: 10.1007/s00262-013-1403-0 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Tse BW, Russell PJ, Lochner M, Forster I, Power CA (2011) IL-18 inhibits growth of murine orthotopic prostate carcinomas via both adaptive and innate immune mechanisms. PLoS ONE 6(9):e24241. doi: 10.1371/journal.pone.0024241 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, Craft J, Yin Z (2003) Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med 198(3):433–442. doi: 10.1084/jem.20030584 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189. doi: 10.1189/jlb.0603252 PubMedCrossRefGoogle Scholar
  9. 9.
    Schmitt MJ, Philippidou D, Reinsbach SE, Margue C, Wienecke-Baldacchino A, Nashan D, Behrmann I, Kreis S (2012) Interferon-gamma-induced activation of Signal Transducer and Activator of Transcription 1 (STAT1) up-regulates the tumor suppressing microRNA-29 family in melanoma cells. Cell Commun Signal 10(1):41. doi: 10.1186/1478-811X-10-41 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Shin EC, Shin WC, Choi Y, Kim H, Park JH, Kim SJ (2001) Effect of interferon-gamma on the susceptibility to Fas (CD95/APO-1)-mediated cell death in human hepatoma cells. Cancer Immunol Immunother 50(1):23–30PubMedCrossRefGoogle Scholar
  11. 11.
    Street D, Kaufmann AM, Vaughan A, Fisher SG, Hunter M, Schreckenberger C, Potkul RK, Gissmann L, Qiao L (1997) Interferon-gamma enhances susceptibility of cervical cancer cells to lysis by tumor-specific cytotoxic T cells. Gynecol Oncol 65(2):265–272. doi: 10.1006/gyno.1997.4667 PubMedCrossRefGoogle Scholar
  12. 12.
    Caretto D, Katzman SD, Villarino AV, Gallo E, Abbas AK (2010) Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol 184(1):30–34. doi: 10.4049/jimmunol.0903412 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Hayakawa Y, Takeda K, Yagita H, Smyth MJ, Van Kaer L, Okumura K, Saiki I (2002) IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood 100(5):1728–1733PubMedGoogle Scholar
  14. 14.
    Palladino I, Salani F, Ciaramella A, Rubino IA, Caltagirone C, Fagioli S, Spalletta G, Bossu P (2012) Elevated levels of circulating IL-18BP and perturbed regulation of IL-18 in schizophrenia. J Neuroinflammation 9:206. doi: 10.1186/1742-2094-9-206 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Fujita K, Ewing CM, Isaacs WB, Pavlovich CP (2011) Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status. Int J Cancer 129(2):424–432. doi: 10.1002/ijc.25705 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ray M, Hostetter DR, Loeb CR, Simko J, Craik CS (2012) Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis. Prostate 72(8):846–855. doi: 10.1002/pros.21486 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Leitzmann MF, Stampfer MJ, Michaud DS, Augustsson K, Colditz GC, Willett WC, Giovannucci EL (2004) Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 80(1):204–216PubMedGoogle Scholar
  18. 18.
    McEntee MF, Ziegler C, Reel D, Tomer K, Shoieb A, Ray M, Li X, Neilsen N, Lih FB, O’Rourke D, Whelan J (2008) Dietary n-3 polyunsaturated fatty acids enhance hormone ablation therapy in androgen-dependent prostate cancer. Am J Pathol 173(1):229–241. doi: 10.2353/ajpath.2008.070989 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Irons R, Fritsche KL (2005) Omega-3 polyunsaturated fatty acids impair in vivo interferon- gamma responsiveness via diminished receptor signaling. J Infect Dis 191(3):481–486. doi: 10.1086/427264 PubMedCrossRefGoogle Scholar
  20. 20.
    Kang JX, Wang J (2005) A simplified method for analysis of polyunsaturated fatty acids. BMC Biochem 6:5. doi: 10.1186/1471-2091-6-5 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408. doi: 10.1006/meth.2001.1262 PubMedCrossRefGoogle Scholar
  22. 22.
    Hobeika AC, Etienne W, Cruz PE, Subramaniam PS, Johnson HM (1998) IFNgamma induction of p21WAF1 in prostate cancer cells: role in cell cycle, alteration of phenotype and invasive potential. Int J Cancer 77(1):138–145PubMedCrossRefGoogle Scholar
  23. 23.
    Kominsky SL, Hobeika AC, Lake FA, Torres BA, Johnson HM (2000) Down-regulation of neu/HER-2 by interferon-gamma in prostate cancer cells. Cancer Res 60(14):3904–3908PubMedGoogle Scholar
  24. 24.
    Igney FH, Krammer PH (2002) Immune escape of tumors: apoptosis resistance and tumor counterattack. J Leukoc Biol 71(6):907–920PubMedGoogle Scholar
  25. 25.
    Selleck WA, Canfield SE, Hassen WA, Meseck M, Kuzmin AI, Eisensmith RC, Chen SH, Hall SJ (2003) IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach. Mol Ther 7(2):185–192PubMedCrossRefGoogle Scholar
  26. 26.
    Hastie C (2008) Interferon gamma, a possible therapeutic approach for late-stage prostate cancer? Anticancer Res 28(5B):2843–2849PubMedGoogle Scholar
  27. 27.
    He YF, Wang XH, Zhang GM, Chen HT, Zhang H, Feng ZH (2005) Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy. Cancer Immunol Immunother 54(9):891–897. doi: 10.1007/s00262-004-0654-1 PubMedCrossRefGoogle Scholar
  28. 28.
    Dinarello CA (2000) Targeting interleukin 18 with interleukin 18 binding protein. Ann Rheum Dis 59(Suppl 1):17–20CrossRefGoogle Scholar
  29. 29.
    Golab J (2000) Interleukin 18–interferon gamma inducing factor–a novel player in tumour immunotherapy? Cytokine 12(4):332–338. doi: 10.1006/cyto.1999.0563 PubMedCrossRefGoogle Scholar
  30. 30.
    Micallef MJ, Tanimoto T, Kohno K, Ikeda M, Kurimoto M (1997) Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma. Cancer Res 57(20):4557–4563PubMedGoogle Scholar
  31. 31.
    Begin ME, Ells G, Das UN, Horrobin DF (1986) Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 77(5):1053–1062PubMedGoogle Scholar
  32. 32.
    Corsetto PA, Montorfano G, Zava S, Jovenitti IE, Cremona A, Berra B, Rizzo AM (2011) Effects of n-3 PUFAs on breast cancer cells through their incorporation in plasma membrane. Lipids Health Dis 10:73. doi: 10.1186/1476-511X-10-73 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Yang T, Fang S, Zhang HX, Xu LX, Zhang ZQ, Yuan KT, Xue CL, Yu HL, Zhang S, Li YF, Shi HP, Zhang Y (2013) N-3 PUFAs have antiproliferative and apoptotic effects on human colorectal cancer stem-like cells in vitro. J Nutr Biochem 24(5):744–753. doi: 10.1016/j.jnutbio.2012.03.023 PubMedCrossRefGoogle Scholar
  34. 34.
    Feng C, Keisler DH, Fritsche KL (1999) Dietary omega-3 polyunsaturated fatty acids reduce IFN-gamma receptor expression in mice. J Interferon Cytokine Res 19(1):41–48. doi: 10.1089/107999099314405 PubMedCrossRefGoogle Scholar
  35. 35.
    Bonilla DL, Ly LH, Fan YY, Chapkin RS, McMurray DN (2010) Incorporation of a dietary omega 3 fatty acid impairs murine macrophage responses to Mycobacterium tuberculosis. PLoS ONE 5(5):e10878. doi: 10.1371/journal.pone.0010878 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Ramana CV, Gil MP, Schreiber RD, Stark GR (2002) Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23(2):96–101PubMedCrossRefGoogle Scholar
  37. 37.
    Valledor AF, Sanchez-Tillo E, Arpa L, Park JM, Caelles C, Lloberas J, Celada A (2008) Selective roles of MAPKs during the macrophage response to IFN-gamma. J Immunol 180(7):4523–4529PubMedCrossRefGoogle Scholar
  38. 38.
    Matsuzawa T, Kim BH, Shenoy AR, Kamitani S, Miyake M, Macmicking JD (2012) IFN-gamma elicits macrophage autophagy via the p38 MAPK signaling pathway. J Immunol 189(2):813–818. doi: 10.4049/jimmunol.1102041 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Nakanishi M, Rosenberg DW (2006) Roles of cPLA2alpha and arachidonic acid in cancer. Biochim Biophys Acta 1761(11):1335–1343. doi: 10.1016/j.bbalip.2006.09.005 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Yang P, Cartwright CA, Li J, Wen S, Prokhorova IN, Shureiqi I, Troncoso P, Navone NM, Newman RA, Kim J (2012) Arachidonic acid metabolism in human prostate cancer. Int J Oncol 41(4):1495–1503. doi: 10.3892/ijo.2012.1588 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Sakai M, Kakutani S, Horikawa C, Tokuda H, Kawashima H, Shibata H, Okubo H, Sasaki S (2012) Arachidonic acid and cancer risk: a systematic review of observational studies. BMC Cancer 12:606. doi: 10.1186/1471-2407-12-606 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Thomasz L, Oglio R, Rossich L, Villamar S, Perona M, Salvarredi L, Dagrosa A, Pisarev MA, Juvenal GJ (2013) 6 Iodo-delta-lactone: a derivative of arachidonic acid with antitumor effects in HT-29 colon cancer cells. Prostaglandins Leukot Essent Fatty Acids 88(4):273–280. doi: 10.1016/j.plefa.2013.01.002 PubMedCrossRefGoogle Scholar
  43. 43.
    Rietjens IM, van Tilburg CA, Coenen TM, Alink GM, Konings AW (1987) Influence of polyunsaturated fatty acid supplementation and membrane fluidity on ozone and nitrogen dioxide sensitivity of rat alveolar macrophages. J Toxicol Environ Health 21(1–2):45–56. doi: 10.1080/15287398709531001 PubMedCrossRefGoogle Scholar
  44. 44.
    Brown M, Anderson KM, Patel H, Hopfinger AJ, Harris JE (1992) Eicosatetraynoic and arachidonic acid-induced changes in cell membrane fluidity consonant with differences in computer-aided design-structures. Biochim Biophys Acta 1105(2):285–290PubMedCrossRefGoogle Scholar
  45. 45.
    Mancini AD, Poitout V (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol Metab 24(8):398–407. doi: 10.1016/j.tem.2013.03.003 PubMedCrossRefGoogle Scholar
  46. 46.
    Mobraten K, Haug TM, Kleiveland CR, Lea T (2013) Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health Dis 12:101. doi: 10.1186/1476-511X-12-101 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler DC, Moorhead JF, Varghese Z (2005) EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism. Kidney Int 67(3):867–874. doi: 10.1111/j.1523-1755.2005.00151.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Xiaofeng Wang
    • 1
  • Andrew Breeze
    • 2
  • Marianna Kulka
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Agricultural, Food and Nutritional ScienceUniversity of AlbertaEdmontonCanada
  2. 2.National Research Council CanadaEdmontonCanada
  3. 3.Department of Medical Microbiology and ImmunologyUniversity of AlbertaEdmontonCanada
  4. 4.National Institute for NanotechnologyEdmontonCanada

Personalised recommendations