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Abstract. Piceatannol has potent anti-inflammatory, immunomodulatory, anticancer and antiproliferative effects. However, little is known about the mechanism by which piceatannol inhibits invasion and metastasis. The aim of the current study was to investigate the effects of piceatannol on the expression of matrix metalloproteinase-9 (MMP-9) in DU145 human prostate cancer cells. The results revealed that MMP-9 activity was significantly increased in response to tumor necrosis factor-α (TNF-α). However, treatment with piceatannol reversed TNF-α-and MMP-9-induced gelatin zymography and its gene expression. In addition, a Matrigel invasion assay determined that piceatannol reduces the TNF-α-induced invasion of DU145 cells. Nuclear factor-κ B (NF-κB) is a significant transcription factor that regulates numerous genes involved in tumor cell invasion and metastasis. Therefore, whether piceatannol acts on NF-κB to regulate MMP-9 gene expression was analyzed. The results revealed that piceatannol attenuates MMP-9 gene expression via the suppression of NF-κB activity. Using a specific NF-κB inhibitor, pyrrolidine dithiocarbamate, it was confirmed that TNF-α-induced MMP-9 gene expression is primarily regulated by NF-κB activation. Piceatannol inhibited NF-κB activity by suppressing nuclear translocation of the NF-κB p65 and p50 subunits. Furthermore, TNF-α-induced Akt phosphorylation was significantly downregulated in the presence of piceatannol. The Akt inhibitor LY294002 caused a significant decrease in TNF-α-induced NF-κB activity and MMP-9 gene expression. Overall, these data suggest that piceatannol inhibits TNF-α-induced invasion by suppression of MMP-9 activation via the Akt-mediated NF-κB pathway in DU145 prostate cancer cells.

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Purpose: To determine whether the methanol extract of Myelophycus caespitosus (MEMC) downregulates the expression of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) together with Western blot analysis was used to evaluate the expression of pro-inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) as well as their regulatory genes such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), in LPS-stimulated BV2 microglial cells. The level of NO production was analyzed using Griess reaction. The release of PGE2 was determined using sandwich enzyme-linked immunosorbent assay. The DNA-binding activity of nuclear factor-κB (NF-κB) was measured by electrophoretic mobility shift assay. Results: MEMC inhibited LPS-induced pro-inflammatory mediators, NO and PGE2, as well as their respective genes, iNOS and COX-2, at both protein and mRNA levels, without any significant cytotoxicity. Treatment with MEMC also substantially reduced the LPS-induced DNA-binding activity of NF-κB and nuclear translocation of NF-κB subunits p65 and p50 via the inhibition of IκBα phosphorylation and degradation. MEMC promoted dephosphorylation of Akt that subsequently suppressed the DNA-binding activity of NF-κB in LPS-stimulated BV2 microglial cells. Conclusion: Collectively, these data suggest that MEMC attenuates expression of pro-inflammatory mediators such as NO and PGE2 by suppression of their regulatory genes through the inhibition of Aktmediated NF-κB activity.