Antimetastatic Effects and Mechanisms of Apo-8′-Lycopenal, an Enzymatic Metabolite of Lycopene, Against Human Hepatocarcinoma SK-Hep-1 Cells

Abstract

Lycopene is primarily metabolized by carotenoid monoxygenase II into apo-8′- and apo-12′-lycopenal in the rat liver. Although lycopene possesses antimetastatic activity in a highly invasive hepatoma SK-Hep-1 cell line, little is known whether its metabolites have a similar effect. In this study, we investigated the antimetastatic effects of apo-8′-lycopenal (1–10 μM) in comparison with lycopene (10 μM) in SK-Hep-1 cells. We found that both apo-8′-lycopenal and lycopene inhibited the invasion and migration of SK-Hep-1 cells, and the effect of apo-8′-lycopenal was stronger than that of lycopene at the same concentration (10 μM). Mechanistically, apo-8′-lycopenal: 1) decreased the activities and protein expression of metalloproteinase-2 (MMP-2) and −9; 2) increased the protein expression of nm23-H1 and the tissue inhibitor of MMP (TIMP)-1 and −2; 3) suppressed protein expression of Rho small GTPases; and 4) inhibited focal adhesion kinase-mediated signaling pathway, such as ERK/p38 and PI3K-Akt axis. Overall, these results demonstrate that apo-8′-lycopenal possesses antimetastatic activity in SK-Hep-1 cells and that this effect is stronger than that of lycopene, suggesting that the antimetastatic effect may be attributed, at least in part, to its metabolites such as apo-8′-lycopenal.

ACKNOWLEDGMENT

We thank Prof. John W. Erdman, Jr. for providing apo-8′-lycopenal and for reviewing the manuscript.