Lycopene inhibits matrix metalloproteinase-9 expression and down-regulates the binding activity of nuclear factor-kappa B and stimulatory protein-1.
The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as hepatoma. Although lycopene has been shown to inhibit metastasis, its mechanism of action is poorly understood. Here, we used SK-Hep-1 cells (from a human hepatoma) to test whether lycopene exerts its anti-invasion activity via down-regulation of the expression of matrix metalloproteinase (MMP)-9, an important enzyme in the degradation of basement membrane in cancer invasion. The activity and expressions of MMP-9 protein and mRNA were detected by gelatin zymography, Western blotting and RT-PCR, respectively. The binding abilities of nuclear factor-kappa B (NF-kappaB), activator protein-1 and stimulatory protein-1 (Sp1) to the binding sites in the MMP-9 promoter were measured by the electrophoretic mobility shift assay. We showed that lycopene (1-10 microM) significantly inhibited SK-Hep-1 invasion (P<.05) and that this effect correlated with the inhibition of MMP-9 at the levels of enzyme activity (r(2)=.94, P<.001), protein expression (r(2)=.80, P=.007) and mRNA expression (r(2)=.94, P<.001). Lycopene also significantly inhibited the binding abilities of NF-kappaB and Sp1 and decreased, to some extent, the expression of insulin-like growth factor-1 receptor (IGF-1R) and the intracellular level of reactive oxygen species (P<.05). The antioxidant effect of lycopene appeared to play a minor role in its inhibition of MMP-9 and invasion activity of SK-Hep-1 cells because coincubation of cells with lycopene plus hydrogen peroxide abolished the antioxidant effect but did not significantly affect the anti-invasion ability of lycopene. Thus, lycopene decreases the invasive ability of SK-Hep-1 cells by inhibiting MMP-9 expression and suppressing the binding activity of NF-kappaB and Sp1. These effects of lycopene may be related to the down-regulation of IGF-1R, while the antioxidant activity of lycopene appears to play a minor role.
Huang
Chin-Shiu
CS
Department of Food Science and Biotechnology, National Chung-Hsing University, Taichung 402, Taiwan, Republic of China.
Fan
Yang-En
YE
Lin
Chen-Yu
CY
Hu
Miao-Lin
ML
D016588:Anticarcinogenic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular; D002338:Carotenoids / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D000077276:Lycopene; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D012334:RNA, Neoplasm / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D012334:RNA, Neoplasm; D017382:Reactive Oxygen Species; D002338:Carotenoids; D017526:Receptor, IGF Type 1; D020780:Matrix Metalloproteinase 9; D000077276:Lycopene