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Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-κB and AP-1 via ERK signaling pathway in A549 human lung cancer cells

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Abstract

This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell–matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBα (IκBα), and the nuclear levels of nuclear factor kappa B (NF-κB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-κB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.

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Abbreviations

TPA:

12-O-tetradecanoylphorbol-13-acetate

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/Akt:

Phosphoinositide 3-kinase/protein kinase B

NF-κB:

Nuclear factor kappa B

AP-1:

Activator protein-1

IκB:

Inhibitor of NF-κB

IκK:

IκB kinase

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Acknowledgment

This work was supported by the grant from the Subsidized Project of the Chung Hwa University, Tainan, Taiwan (97-HT-08011).

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan

    Jiunn-Min Shieh

  2. Department of Medical Technology and Institute of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan

    Tai-An Chiang

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

    Wen-Teng Chang, Yi-Chieh Lee, Guan-Yu Huang & Yuan-Wei Shih

  4. Department of Neurology, Kuo General Hospital, Tainan, 700, Taiwan

    Chang-Hung Chao

  5. Taipei Municipal Song Shan Senior High School, Taipei, 110, Taiwan

    You-Xin Shih

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  1. Jiunn-Min Shieh
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Correspondence to Yuan-Wei Shih.

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Shieh, JM., Chiang, TA., Chang, WT. et al. Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-κB and AP-1 via ERK signaling pathway in A549 human lung cancer cells. Mol Cell Biochem 335, 181–193 (2010). https://doi.org/10.1007/s11010-009-0254-7

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  • DOI: https://doi.org/10.1007/s11010-009-0254-7

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