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  • Original Paper
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DIM stimulates IFNγ gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways

Oncogene volume 24, pages 2343–2353 (2005)Cite this article

Abstract

3,3′-Diindolylmethane (DIM) is a promising anticancer agent derived from Brassica vegetables, but the mechanisms of DIM action are largely unknown. We have shown that DIM can upregulate the expression and stimulate the secretion of interferon-gamma (IFNγ) in the human MCF-7 breast cancer cell line. This novel effect may provide important clues to explain the anticancer effects of DIM because it is well known that IFNγ plays an important role in preventing the development of primary and transplanted tumors. Utilizing promoter deletions, we show here that the region between −108 and −36 bp in the IFNγ promoter, which contains two conserved and essential regulatory elements, is required for DIM-induced IFNγ expression. DIM activates both JNK and p38 pathways, induces the phosphorylation of c-Jun and ATF-2, and increases the binding of the homodimer or heterodimer of c-Jun/ATF-2 to the proximal AP-1·CREB-ATF-binding element. Moreover, studies with specific enzyme inhibitors showed that up-stream Ca2+-dependent kinase(s) is required for the inducing effects of DIM in MCF-7 cells. These results establish that DIM-induced IFNγ expression in human breast tumor cells is mediated by activation of both JNK and p38 pathways, which is ultimately dependent on intracellular calcium signaling.

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Abbreviations

DIM:

3,3′-diindolylmethane

I3C:

indole-3-carbinol

IFNγ:

interferon-gamma

DMSO:

dimethylbenzanthracene

PMA:

phorbol 12-myristate 13-acetate

CsA:

cyclosporin A

CN:

calcineurin

BAPTA:

1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester

MAPK:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

PKC:

protein kinase C

PKA:

protein kinase A

CAT:

chloramphenicol acetyltransferase

EMSA:

electrophoretic mobility shift assay

Sp1:

promoter-specific transcription factor 1

Sp3:

promoter-specific transcription factor 3

ER:

endoplasmic reticulum

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Acknowledgements

We are grateful to Dr Christopher B Wilson for generously providing the constructs, pIFN-538, pIFN-339, pIFN-108, and plasmids, ATF-2FL, ATF-2BR, wild-type c-Jun, and c-JunΔBR. We are particularly indebted to Dr Howard A Young for kindly providing the plasmids 3 × (−66/−47)CAT, 3 × (−96/−75)CAT, (−108 to −36)CAT, and (−108 to −36)ΔΔ′CAT. We also thank Dr Richard H Goodman for providing the plasmids wild-type CREB and dominant-negative kCREB. This work was supported by the Department of Defense, Army Breast Cancer Research Program Grant DAMDI7-96-1-6149 (BC990908), and by Grants CA69056 and CA102360 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Nutritional Sciences and Toxicology, University of California, 119 Morgan Hall, Berkeley, CA, 94720-3104, USA

    Ling Xue & Leonard F Bjeldanes

  2. Department of Molecular and Cell Biology, University of California, 119 Morgan Hall, Berkeley, CA, 94720-3104, USA

    Gary L Firestone

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Correspondence to Leonard F Bjeldanes.

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Xue, L., Firestone, G. & Bjeldanes, L. DIM stimulates IFNγ gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene 24, 2343–2353 (2005). https://doi.org/10.1038/sj.onc.1208434

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