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Acacetin inhibits the invasion and migration of human non-small cell lung cancer A549 cells by suppressing the p38α MAPK signaling pathway

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Abstract

Lung cancer is one of the most common malignancies in the world and its metastasis is the major cause of death in cancer patients. Acacetin (5,7-dihydroxy-4′-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. The effect of acacetin on invasion and migration in human NSCLC A549 cells was investigated. First, the result demonstrated acacetin could exhibit an inhibitory effect on the abilities of the adhesion, morphology/actin cytoskeleton arrangement, invasion, and migration by cell–matrix adhesion assay, immunofluorescence assay, Boyden chamber assay, and wound-healing assay. Molecular data showed that the effect of acacetin in A549 cells might be mediated via sustained inactivation of the phosphorylation of mixed-lineage protein kinase 3 (MLK3), mitogen-activated protein kinase kinases 3/6 (MKK3/6), and p38α MAPK signal involved in the downregulation of the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (u-PA). Next, acacetin significantly decreased in the 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, the treatment with acacetin to A549 cells also leads to a concentration-dependent inhibition on the binding abilities of NF-κB and activator protein-1 (AP-1). Furthermore, the treatment of specific inhibitor for p38 MAPK (SB203580) to A549 cells could cause reduced activities of MMP-2/9 and u-PA. In addition, acacetin significantly decreased the levels of phospho-p38α MAPK, MMP-2/9, and u-PA in p38α-cDNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. Our results revealed the anti-migration and anti-invasion effects of acacetin, which may act as a promising therapeutic agent for the treatment of lung cancer.

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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

MKK3/6:

Mitogen-activated protein kinase kinase

MLK3:

Mixed-lineage protein kinase 3

NF-κB:

Nuclear factor kappa B

IκBα:

Inhibitor of kappaBα

AP-1:

Activator protein-1

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Acknowledgment

This work was supported by the grant from the Subsidized Project of the Kaohsiung Armed Forces General Hospital (9929) and Chung Hwa University of Medical Technology (98-HT-08005).

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Authors and Affiliations

  1. Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung, 802, Taiwan, ROC

    Shang-Tao Chien & Su-Shun Lin

  2. E-Chyun Dermatology Clinic, Tainan, 701, Taiwan, ROC

    Cheng-Kun Wang

  3. Department of Cosmetic Science, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan, ROC

    Cheng-Kun Wang

  4. Department of Gynecology, Yongkang Veterans Hospital, Tainan, 710, Taiwan, ROC

    Yuan-Bin Lee

  5. Department of Optometry, Chung Hwa University of Medical Technology, Tainan, 717, Taiwan, ROC

    Kun-Shiang Chen

  6. Department of Thoracic Surgery, Chi Mei Medical Center, No. 901, Jhong-Hua Road, Yong-Kang, Tainan, 710, Taiwan, ROC

    Yao Fong

  7. 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, ROC

    Yuan-Wei Shih

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  1. Shang-Tao Chien
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Correspondence to Yao Fong or Yuan-Wei Shih.

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Chien, ST., Lin, SS., Wang, CK. et al. Acacetin inhibits the invasion and migration of human non-small cell lung cancer A549 cells by suppressing the p38α MAPK signaling pathway. Mol Cell Biochem 350, 135–148 (2011). https://doi.org/10.1007/s11010-010-0692-2

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  • DOI: https://doi.org/10.1007/s11010-010-0692-2

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