Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells

Mol Cell Biochem. 2010 Jan;333(1-2):169-80. doi: 10.1007/s11010-009-0217-z. Epub 2009 Jul 26.

Abstract

Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to possess some anti-cancer and anti-inflammation capabilities. In this study, fisetin has exhibited inhibitory effects on the adhesion, migration, and invasion ability of a highly metastatic PC-3 cells under non-cytotoxic concentrations. Gelatin zymography assay showed that fisetin inhibited the matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities. Our result also showed that fisetin could inhibit the phosphorylation of c-Jun N-terminal kinase 1 and 2 (JNK1/2) and Akt. Moreover, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun, and the binding abilities of NF-kappaB and activator protein-1 (AP-1). Also, the results showed that the protein and mRNA levels of MMP-2 and MMP-9 were significantly reduced by Western blot and semi-quantitative RT-PCR. Further, treating specific inhibitors for PI3K (Wortmannin) or JNK (SP600125) to PC-3 cells could reduce the protein expressions of MMP-2 and MMP-9. These results showed fisetin could inhibit the metastatic ability of PC-3 by reducing MMP-2 and MMP-9 expressions through suppressing phosphoinositide 3-kinase/Akt (PI3K/Akt) and JNK signaling pathways. This suggested fisetin can serve as a potential candidate for treating cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Flavonoids / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Male
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 9 / genetics*
  • Neoplasm Metastasis / drug therapy*
  • Neoplasm Metastasis / prevention & control
  • Phosphatidylinositol 3-Kinases
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects*

Substances

  • Flavonoids
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • fisetin