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

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.

• Authors: Hui Ling, Yaochun Zhang, Ka-Yun Ng, Eng-Hui Chew
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 126 Issue 3 Pg. 609-20 (Apr 2011) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 20521099 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• NF-kappa B
• Triterpenes
• p38 Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 9
• pachymic acid

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Survival
• Densitometry (methods)
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Matrix Metalloproteinase 9 (metabolism)
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Time Factors
• Transcriptional Activation
• Triterpenes (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)