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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Agricultural, Food and Nutritional Science, University of Alberta, 116 Street and 85 Avenue, Edmonton, AB, T6G 2R3, Canada

    Xiaofeng Wang

  2. National Research Council Canada, 11421 Saskatchewan Drive, Edmonton, AB, T6G 2M9, Canada

    Andrew Breeze & Marianna Kulka

  3. Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada

    Marianna Kulka

  4. National Institute for Nanotechnology, 11421 Saskatchewan Drive, Edmonton, AB, T6G 2M9, Canada

    Marianna Kulka

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  1. Xiaofeng Wang
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Correspondence to Marianna Kulka.

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Wang, X., Breeze, A. & Kulka, M. N-3 polyunsaturated fatty acids inhibit IFN-γ-induced IL-18 binding protein production by prostate cancer cells. Cancer Immunol Immunother 64, 249–258 (2015). https://doi.org/10.1007/s00262-014-1630-z

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