Carcinogenesis Advance Access originally published online on May 15, 2009
Carcinogenesis 2009 30(7):1234-1242; doi:10.1093/carcin/bgp121
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Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells
Department of Seafood Science, National Kaohsiung Marine University, No. 142, Hai-Chuan Road, Nan-Tzu, Kaohsiung 811, Taiwan
1 Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402, Taiwan
2 Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
3 Sabinsa Corporation, 70 Ethel Road West Unit 6, Piscataway, NJ 08854, USA
4 Department of Food Science, Cook College, Rutgers University, New Brunswick, NJ 08901-8520, USA
* To whom correspondence should be addressed. Tel: +886 7 361 7141; Fax: +886 7 361 1261; Email: mhpan{at}mail.nkmu.edu.tw
Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG2 cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG2 cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-
B) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG2 cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-B and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG2 cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.
Abbreviations: AP-1, activator protien-1; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; ERK, extracellular signal-regulated kinase; HPLC, high-performance liquid chromatography; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MET, mesenchymal–epithelial transition; MMP, matrix metalloproteinase; NF-B, nuclear factor-kappa B; PCR, polymerase chain reaction; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; TPA, 12-O-tetradecanoylphorbol 13-acetate; VEGF, vascular endothelial growth factor
Received March 2, 2009; revised May 8, 2009; accepted May 8, 2009.