Lycopene Inhibits Cell Migration and Invasion and Upregulates Nm23-H1 in a Highly Invasive Hepatocarcinoma, SK-Hep-1 Cells

Abstract

The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as prostate cancer and hepatoma. Tumor metastasis is the most important cause of cancer death. Although lycopene was shown to inhibit metastasis, the mechanism underlying this action is not well understood. Here, we tested the possibility that lycopene may inhibit cancer cell metastasis by upregulating the expression of nm23-H1, a metastasis suppressor gene, in SK-Hep-1 cells, a highly invasive hepatoma cell line, and we determined migration and invasion activities and the expression of nm23-H1 protein and mRNA. We showed that lycopene inhibited SK-Hep-1 migration and invasion in a bell-shaped manner, with the highest effect at 5 micromol/L (91 and 63% inhibition for migration and invasion, respectively; P < 0.05). At the same test level (10 micromol/L), lycopene was much more effective than beta-carotene in reducing cell invasion (by approximately 870%). In contrast to the effects on migration and invasion, lycopene enhanced nm23-H1 expression at both the protein and mRNA levels; the effects were also bell shaped, and at 5 micromol/L, lycopene enhanced nm23-H1 protein and mRNA expressions by 220 +/- 33 and 153 +/- 22% (P < 0.01), respectively. These bell-shaped effects of lycopene may be related to autoxidation of lycopene at elevated concentrations (> or =10 micromol/L). Significant correlations existed between nm23-H1 protein expression and migration (r2= 0.78, P < 0.001) and between nm23-H1 protein expression and invasion (r2= 0.84, P < 0.001) in lycopene-treated SK-Hep-1 cells. We conclude that lycopene has significant antimigration and anti-invasion activity, and that this effect is associated with its induction of nm23-H1 expression.

Inhibitory effects of olive oil phenolics on invasion in human colon adenocarcinoma cells in vitro

“…This parabolic trend may be due to autooxidation of the compounds at concentrations 10 lM, as reported in a similar study with lycopene. 18 Further, in a bleomycin assay, hydroxytyrosol has been reported to have pro-oxidant effects at a concentration of 0.01% (w/v), 19 which may account for the parabolic dose respond effect in our invasion assay.…”

Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

“…Park et al [120] demonstrated the inhibitory effect exerted by lycopene in Hep3B cells through mechanisms involving cell cycle arrest in the G0/G1 phase and DNA damage. This tetraterpenoid also effectively displayed antimigration and anti-invasive properties against highly invasive SK-Hep-1 cells which were associated with the increase of the metastasis suppressor gene, nm23-H1 [115] . The study by Hwang and Lee [121] concluded with similar results displaying lycopene's inhibitory effects on adhesion, invasion and migration of SK-Hep-1 cells.…”

“…Antioxidant mechanisms 2.5-20 μmol/L Kozuki et al [114] Inhibited the migration of SK-Hep-1 cells 1-20 μmol/L Huang et al [115] Delayed the proliferation and improved the differentiation of oval cells obtained from neoplastic liver ↑albumin; ↑fibrinogen; ↑ hapatoglobin 5 μmol/L Wójcik et al [116] Exerted genotoxic and cytotoxic effects in HepG2 cells ↑apoptosis; ↑necrosis; ↑TBARS 4-8 μmol/L Yurtcu et al [117] Fucoxanthin Inhibited the growth of HepG2 cells ⊥G0/G1; ↓cyclin D1, D3; ↓cdk4; ↓pRb 10-50 μmol/L Das et al [118] Exhibited antiproliferative effect against SK-Hep-1 cells ↑apoptosis; ⊥G0-G1; ↑GJIC; ↑Cx43; ↑Cx32; ↓pJNK; ↓pERK; ↑[Ca] [119] Lycopene Suppressed the invasive property of AH109A cells [114] Induced an inhibitory effect on the growth of Hep3b cells [120] Displayed antimigration and anti-invasive activity in SK-Hep-1 cells [115] Inhibited adhesion, invasion and migration of SK-Hep-1 cells ↓MMP-9, -2 0.1-50 μmol/L Hwang et al [121] Inhibited SK-Hep-1 cell invasion ↓MMP-9; ↓NF-κB; ↑IκBα; ↓Sp1; ↓IGF-1R; ↓ROS 1-10 μmol/L Huang et al [122] Sesquiterpenes α-Bisabolbol Induced cytoxicity in HepG2 cells ↑apoptosis; ↑caspase-8, -9; ↑cyt. c; ↑Bax; ↑Bak; ↓Bcl-2; ↑p53; ↑NF-κB; ↑Fas [123] Dehydrocostuslactone…”

“…Both carotenoids inhibited AH109A invasion through antioxidant mechanisms [114] . Huang et al [115] showed that β-carotene effectively inhibited cell migration in SK-Hep-1 cell lines. The effects of astaxanthin and β-carotene on the proliferation and differentiation of isolated rat oval cells were investigated.…”

Obligatory role for phospholipase C-γ1 in villin-induced epithelial cell migration

“…Several studies have demonstrated that increased cell migration does not always imply increased invasiveness (21,41). Hence, we elected to examine the role of tyrosinephosphorylated villin and PLC-␥ 1 in transmembrane migration of cells through Matrigel.…”