Terminalia catappaExerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-κB and AP-1 Activity

Abstract

High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. Previous studies have identified that Terminalia catappa leaf extracts (TCE) exert hepatoprotective, antioxidative, antiinflammatory, anticancer, and antimetastatic activities. However, the effects of TCE on HCC and the underlying molecular mechanisms of its activities have yet to be fully elucidated. The present study's findings demonstrate that TCE concentration dependently inhibits human HCC migration/invasion. Zymographic and western blot analyses revealed that TCE inhibited the activities and expression of matrix metalloproteinase-9 (MMP-9). Assessment of mRNA levels, using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR, and promoter assays confirmed the inhibitory effects of TCE on MMP-9 expression in HCC cells. The inhibitory effects of TCE on MMP-9 proceeded by upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as suppressing nuclear translocation and DNA binding activity of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) on the MMP-9 promoter in Huh7 cells. In conclusion, TCE inhibits MMP-9 expression and HCC cell metastasis and, thus, has potential use as a chemopreventive agent. Its inhibitory effects are associated with downregulation of the binding activities of the transcription factors NF-κB and AP-1.

Selaginella tamariscina Attenuates Metastasis via Akt Pathways in Oral Cancer Cells

“…MMP-2 and MMP-9 are the most extensively studied of the MMP family because of their high association with cancer migration and invasion [5]. Several previous studies have indicated that natural products inhibit cancer metastasis by inhibiting MMP-2 and MMP-9 expression [23,26]. Our results indicate that Selaginella tamariscina inhibited MMP-2 and MMP-9 enzyme activity, as well as protein expression.…”

“…Previous studies have shown that MMP promoters are regulated by several transcription factors, such as AP-1, NFκB, CREB, and SP-1 [23,25,26]. We performed a chromatin immunoprecipitation (ChIP) assay to evaluate the involvement of transcription factors in the inhibitory effects of Selaginella tamariscina on MMP-2 and MMP-9 activity (Figure 5A and 5B).…”

“…Numerous medicinal plants have been studied for anticancer applications, such as Dioscorea nipponica Makino [23] and Terminalia Catappa [26]. Over the past decade, Selaginella tamariscina has become a traditional treatment for various diseases [14,15,18,19].…”

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).…”

An updated review of Terminalia catappa

“…This inhibition is ensued by upregulating the tissue inhibitor of metalloproteinase-1 (TIMP-1); in addition, it suppresses nuclear translocation and downregulates the DNA binding activity of nuclear factor-kappa B (NF- κB) and activator protein-1 (AP-1) on the MMP-9 promoter in Human hepato cellular carcinoma cell line (Huh 7 cells). [37] In persistence, the treatment of Huh7 cells with T. catappa notably decreases the activities of protein levels as well the mRNA levels of urokinase-type plasminogen activator (u-PA). T. catappa inhibits the transcription protein of nuclear factors stimulating protein-1 (SP-1), NF-κB, and also inhibits the effects of u-PA by decreasing the phosphorylation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway.…”