Bachmeier Beatrice E, Mohrenz Isabelle V, Mirisola Valentina, Schleicher Erwin, Romeo Francesco, Höhneke Clara, Jochum Marianne, Nerlich Andreas G, Pfeffer Ulrich
Department of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University Munich, D-80336 München, Germany.
Carcinogenesis. 2008 Apr;29(4):779-89. doi: 10.1093/carcin/bgm248. Epub 2007 Nov 13.
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.
膳食抗氧化剂姜黄素已被提议用于癌症化学预防，因为它可诱导细胞凋亡并抑制乳腺癌转移的形成。姜黄素通过抑制κB抑制蛋白（IkappaB）的磷酸化发挥作用，这进而减少了核因子κB（NFkappaB）的核转位，NFkappaB是一种与炎症和细胞存活相关的转录因子。然而，目前尚不清楚这种强大的抗转移作用是否完全可以通过抑制NFkappaB来解释。在此，我们使用微阵列基因表达分析方法研究了姜黄素（IC(50) = 17 μM）对MDA-MB-231乳腺癌细胞的影响。在62个表达显著改变的基因中，我们发现两种炎症细胞因子CXCL1和CXCL2（Groalpha和Grobeta）表达下调。通过定量实时逆转录-聚合酶链反应、蛋白质免疫印迹和酶联免疫吸附测定对微阵列结果进行的进一步验证表明，姜黄素在24小时后损害CXCL1和CXCL2的转录并降低相应的蛋白质水平。使用小干扰RNA技术，我们阐明了潜在的分子机制，发现CXCL1和CXCL2信使RNA水平的降低依赖于NFkappaB，并且需要完整的IkappaBalpha表达。此外，CXCL1和CXCL2的沉默导致几个促进转移的基因下调，其中我们发现了细胞因子受体CXCR4。因此，我们认为姜黄素介导的CXCL1和CXCL2的减少与转移抑制有关。
