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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

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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-κB), c-Fos, and c-Jun, and the binding abilities of NF-κB 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.

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Abbreviations

MMPs:

Matrix metalloproteinases

u-PA:

Urokinase-type plasminogen activator

ECM:

Extracellular matrix

ERK:

Extracellular signaling-regulating kinase

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

p38 MAPK:

p38 Mitogen-activated protein kinase

PI3K:

Phosphoinositide 3-kinase

NF-κB:

Nuclear factor kappa B

AP-1:

Activator protein-1

IκB:

Inhibitor of NF-κB

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Acknowledgment

This study was supported by the grant from the Subsidized Project of the Chung Hwa University, Tainan, Taiwan (97-HT-08008).

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan

    Chi-Sheng Chien

  2. Division of Urology, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan

    Kun-Hung Shen

  3. Department of Biological Science and Technology, Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, Tainan, 717, Taiwan

    Jau-Shyang Huang & Yuan-Wei Shih

  4. Department of Pulmonary Medicine, Chi Mei Medical Center, Tainan, Taiwan

    Shian-Chin Ko

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  1. Chi-Sheng Chien
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Correspondence to Yuan-Wei Shih.

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Chien, CS., Shen, KH., Huang, JS. et al. 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 333, 169–180 (2010). https://doi.org/10.1007/s11010-009-0217-z

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  • DOI: https://doi.org/10.1007/s11010-009-0217-z

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