Carcinogenesis Advance Access originally published online on November 13, 2007
Carcinogenesis 2008 29(4):779-789; doi:10.1093/carcin/bgm248
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Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NF
B
1 Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University Munich, D-80336 München, Germany
2 Functional Genomics, National Cancer Research Institute, Largo Rosanna Benzi 10, 16132 Genoa, Italy
3 CNR–IEIIT, Torre di Francia, Via de Marini 6, 16149 Genoa, Italy
4 Department of Medicine IV, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany
5 Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genoa, Italy
6 University of Genoa, Via Balbi 2 – 16126 Genoa, Italy
7 Institute of Pathology, Academic Hospital Munich-Bogenhausen, Englschalkingerstr. 77, 80927 Munich, Germany
* To whom correspondence should be addressed: Tel: +49 89 5160 2650; Fax: +49 89 5160 4740; Email: bachmeier{at}med.uni-muenchen.de
The dietary antioxidant 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
B), which in turn reduces the nuclear translocation of nuclear factor kappa B (NFB), an inflammation- and cell survival-related transcription factor. However, it is not clear whether the strong antimetastatic effect can exclusively be explained by inhibition of NFB. Here, we addressed the effects of Curcumin (IC50 = 17 µM) 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
and -β) that were downregulated. Further validation of the microarray results by quantitative real-time reverse transcription–polymerase chain reaction, western blots and enzyme-linked immunosorbent assay revealed that Curcumin impairs transcription of CXCL1 and -2 >24 h and reduces the corresponding proteins. Using small interfering RNA techniques, we elucidated the underlying molecular mechanism revealing that reduction of CXCL1 and -2 messenger RNA levels is NFB dependent and requires intact IB expression. Moreover, CXCL1 and -2 silencing leads to downregulation 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.
Abbreviations: HMOX1, hemeoxygenase-1; IB, inhibitor of kappa B; mRNA, messenger RNA; NFB, nuclear factor kappa B; PTGS2, prostaglandin-endoperoxide synthase 2; qRT–PCR, quantitative real-time reverse transcription–polymerase chain reaction; siRNA, small interfering RNA
Received July 19, 2007; revised October 31, 2007; accepted November 4, 2007.
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