Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB.
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 (IkappaB), which in turn reduces the nuclear translocation of nuclear factor kappa B (NFkappaB), 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 NFkappaB. Here, we addressed the effects of Curcumin (IC(50) = 17 muM) 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 (Groalpha and -beta) 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 NFkappaB dependent and requires intact IkappaBalpha 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.
Bachmeier
Beatrice E
BE
Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University Munich, D-80336 München, Germany. bachmeier@med.uni-muenchen.de
Mohrenz
Isabelle V
IV
Mirisola
Valentina
V
Schleicher
Erwin
E
Romeo
Francesco
F
Höhneke
Clara
C
Jochum
Marianne
M
Nerlich
Andreas G
AG
Pfeffer
Ulrich
U
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000235:genetics*; D054426:Chemokine CXCL2 / Q000235:genetics*; D003474:Curcumin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
D000975:Antioxidants; C475829:CXCL1 protein, human; C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D004273:DNA, Neoplasm; D016328:NF-kappa B; D012334:RNA, Neoplasm; D003474:Curcumin