The Antimetastatic Effects of Resveratrol on Hepatocellular Carcinoma through the Downregulation of a Metastasis-Associated Protease by SP-1 Modulation

Abstract

BackgroundThe mortality and morbidity rates from cancer metastasis have not declined in Taiwan, especially because of hepatocellular carcinoma (HCC). Resveratrol has been shown to have benefits such as cardioprotection, providing antioxidative, anti-inflammatory, anti-cancer properties in previous studies. Therefore, HCC cells were subjected to treatment with resveratrol and then analyzed to determine the effects of resveratrol on the migration and invasion.Methodology and Principal FindingsModified Boyden chamber assays revealed that resveratrol treatment significantly inhibited cell migration and invasion capacities of Huh7 cell lines that have low cytotoxicity in vitro, even at a high concentration of 100 µM. The results of casein zymography and western blotting revealed that the activities and protein levels of the urokinase-type plasminogen activator (u-PA) were inhibited by resveratrol. Western blot analysis also showed that resveratrol inhibits phosphorylation of JNK1/2. Tests of the mRNA level, real-time PCR, and promoter assays evaluated the inhibitory effects of resveratrol on u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay showed that reactive in transcription protein of nuclear factor SP-1 was inhibited by resveratrol.ConclusionsResveratrol inhibits u-PA expression and the metastasis of HCC cells and is a powerful chemopreventive agent. The inhibitory effects were associated with the downregulation of the transcription factors of SP-1 signaling pathways.

Pterostilbene Inhibits the Growth of Human Esophageal Cancer Cells by Regulating Endoplasmic Reticulum Stress

“…Similarly, celastrolinduced growth inhibition and repression of Sp1, Sp3 and Sp4 in bladder cancer cells can be blocked by ROS inhibitors [36]. Importantly, resveratrol inhibits u-PA expression and HCC cell metastasis through the downregulation of Sp-1 [37]. Accordingly, as a natural dimethylated analog of resveratrol, PTE may regulate Sp-1 protein and ROS to exert anti-cancer effects against EC109 cells.…”

Terminalia catappa attenuates urokinase-type plasminogen activator expression through Erk pathways in Hepatocellular carcinoma

“…The survival rate of HCC in Taiwan has not increased primarily because of undamped tumor invasion and metastasis [3,4]. Cancer cells from the primary tumor invade neighboring tissue through the secretion of urokinase-type plasminogen activator (u-PA).…”

Methionine Adenosyltransferase 2B, HuR, and Sirtuin 1 Protein Cross-talk Impacts on the Effect of Resveratrol on Apoptosis and Growth in Liver Cancer Cells

“…RSV has been shown in experimental models to exert chemopreventive and therapeutic efficacy against HCC (21,22). This may be related to its anti-proliferative and pro-apoptotic effects in liver cancer cells; however, the signaling mechanisms involved are still being defined (1, 21, 22).…”