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Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression

  • Preclinical study
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Abstract

Pachymic acid (PA), a lanostane-type triterpenoid derived from Poria cocos, possesses demonstrated anti-inflammatory and anti-cancer activities. Nonetheless, the biological properties and mechanism/s of action of PA remain largely undefined. In this study, the activity of PA against breast cancer cell invasion was evaluated. Invasiveness of human-derived MDA-MB-231 and MCF-7 breast carcinoma cells was suppressed by PA at non-lethal concentrations, which was associated with a decrease in matrix metalloproteinase-9 (MMP-9) secretion as a result of PA-mediated down-regulation of MMP-9 mRNA expression. In order to elucidate the underlying anti-invasive mechanism, the effect of PA on transcription factors activator protein-1 (AP-1) and nuclear factor kappaB (NF-κB) was examined using luciferase-based reporter gene assays. PA was found to bring about a reduction in phorbol 12-myristate 13-acetate (PMA)-induced transcriptional activity of NF-κB, but not that of AP-1. In accord with the luciferase activity data, western blot analysis showed that PA inhibited NF-κB signaling pathway, but did not alter the phosphorylation states of mitogen-activated protein kinases including ERK, JNK, and p38 kinase. The inhibition of PA on NF-κB signaling pathway was further attributed to PA-mediated diminution in PMA-induced degradation of inhibitor of kappaBα (IκBα) through preventing phosphorylation of the upstream signal IκB kinase (IKK). A decrease in p65 nuclear translocation was achieved, which led to attenuation of NF-κB transactivation. Taken together, it was concluded that by targeting NF-κB signaling, PA inhibited breast cancer cell invasion through decreasing MMP-9 expression. PA may thus be potentially exploited for use in tumor metastasis intervention.

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Abbreviations

AP-1:

Activator protein-1

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IκBα:

Inhibitor of kappaBα

IKK:

IκB kinase

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloproteinase

NF-κB:

Nuclear factor kappaB

PA:

Pachymic acid

PKC:

Protein kinase C

PMA:

Phorbol 12-myristate 13-acetate

RT-PCR:

Reverse transcription-polymerase chain reaction

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Acknowledgements

This work was supported by National Institute of Health Grant 5R21CA115269 (K-Y. Ng) and National University of Singapore Academic Research Fund Tier 1 R-148-000-099-112 (E.-H. Chew).

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Republic of Singapore

    Hui Ling, Yaochun Zhang, Ka-Yun Ng & Eng-Hui Chew

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  1. Hui Ling
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  2. Yaochun Zhang
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Correspondence to Ka-Yun Ng or Eng-Hui Chew.

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Ling, H., Zhang, Y., Ng, KY. et al. Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression. Breast Cancer Res Treat 126, 609–620 (2011). https://doi.org/10.1007/s10549-010-0929-5

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