Carcinogenesis Advance Access published online on May 15, 2009
Carcinogenesis, doi:10.1093/carcin/bgp121
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Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells
1 Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan
2 Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402, Taiwan
3 Intitute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
4 Sabinsa Corporation, 70 Ethel Road West Unit 6, Piscataway, NJ 08854
5 Department of Food Science, Cook College, Rutgers University, New Brunswick, New Jersey 08901-8520, USA
* Please send all correspondence to: Dr. Min-Hsiung Pan, Department of Seafood Science, National Kaohsiung Marine University, No. 142, Hai-Chuan Rd, Nan-Tzu, Kaohsiung, Taiwan. Tel. no. (886)-7-361-7141, Fax. no. (886)-7-361-1261, E-mail: mhpan{at}mail.nkmu.edu.tw
Pterostilbene (PS), a natural dimethylated analogue of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, antiproliferation 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 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 VEGF, EGF and EGFR. 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 (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) , c-Jun N-terminal kinases 1/2 (JNK1/2), and phosphatidylinositol 3-kinase (PI3K)/Akt, and PKC which are upstream of NFB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 mg/kg and 250 mg/kg i.p.) after inoculation with HepG2 cells into the tail vein. Presented data reveals that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.
Received March 2, 2009; revised May 8, 2009; accepted May 8, 2009.