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Carcinogenesis Advance Access published online on November 13, 2007
Carcinogenesis, doi:10.1093/carcin/bgm248
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Curcumin Down-Regulates the Inflammatory Cytokines CXCL1 and -2 in Breast Cancer Cells via NF{kappa}B

Beatrice E. Bachmeier1,5,*, Isabelle V. Mohrenz1, Valentina Mirisola2,3, Erwin Schleicher4, Francesco Romeo5,6, Clara Höhneke1, Marianne Jochum1, Andreas G. Nerlich7 and Ulrich Pfeffer2

1 Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University Munich, Germany
2 Functional Genomics, National Cancer Research Institute, Genoa, Italy
3 CNR-IEIIT, Genoa, Italy
4 Department of Medicine IV, University of Tübingen, Germany
5 Advanced Biotechnology Center, Genoa, Italy
6 University of Genoa, Italy
7 Institute of Pathology, Academic Hospital Munich-Bogenhausen, Germany

* corresponding author Beatrice E. Bachmeier, PhD, Dept. of Clinical Chemistry and Clinical Biochemistry, Hospital of Surgery, Ludwig-Maximilians-University, Nussbaumstr. 20, D-80336 München, Germany, Phone: +49-89-5160-2650, Fax: +49-89-5160-4740, e-mail: bachmeier{at}med.uni-muenchen.de

The dietary anti-oxidant Curcumin has been proposed for cancer chemoprevention since it induces apoptosis and inhibits the formation of breast cancer metastases. Curcumin acts through the inhibition of phosphorylation of the Inhibitor of kappa B (I{kappa}B) which in turn reduces the nuclear translocation of Nuclear Factor kappa B (NF{kappa}B), an inflammation and cell survival related transcription factor. However, it is not clear whether the strong anti-metastatic effect can exclusively be explained by inhibition of NF{kappa}B. Here we addressed the effects of Curcumin (IC50=17µM) in MDA-MB 231 breast cancer cells using microarray gene expression analyses. Among the 62 genes whose expression was significantly altered, we found the two inflammatory cytokines CXCL1 and -2 (Gro{alpha} and –ß) that were down-regulated. Further validation of the microarray results by qRT-PCR, Western blots, and ELISA revealed that Curcumin impairs transcription of CXCL1 and -2 over 24 hours and reduces the corresponding proteins. Using siRNA techniques we elucidated the underlying molecular mechanism revealing that reduction of CXCL1 and -2 mRNA levels is NF{kappa}B dependent and requires intact I{kappa}B{alpha} expression. Moreover CXCL1 and -2 silencing leads to down-regulation of several metastasis promoting genes among which we found the cytokine receptor CXCR4. We therefore suggest that the decrease of CXCL1 and -2 mediated by Curcumin is involved in the inhibition of metastasis.

Key Words: Chemoprevention • microarray • breast cancer • metastases • molecular pathway

Received July 19, 2007; revised October 31, 2007; accepted November 4, 2007.


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