Abstract
Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been demonstrated possessing anti-metastatic activity in vitro and in vivo. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored glycoprotein negatively regulating matrix metalloproteinases (MMPs), plays an important role in tumor invasion and metastasis. The present study investigates the regulatory effect of GA on RECK expression and the role of RECK in GA-induced anti-invasion in A549 human lung cancer cells. Our results showed that GA dose-dependently inhibited cell invasion and suppressed A549 experimental lung metastasis in vivo, which was attributed to RECK up-regulation at both protein and mRNA levels. With small interference RNA (siRNA) blocking RECK expression, we found inhibition of RECK decreased the GA-induced inhibition of MMP-2/9, which was in consistent with the attenuated anti-invasive effect of GA. Further study indicated that GA effectively suppressed Histone deacetylase (HDAC) 1/specificity protein (Sp) 1 binding and Sp1 phosphorylation associating with Extracellular signal-regulated kinases (ERK) signaling blocking, leading to RECK up-regulation. Taken together, these data demonstrate that RECK contributes to GA's anti-invasive activity and provide new evidence for GA being served as a therapeutic candidate for cancer metastasis.
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