Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression.
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.
Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.
Hui
H
Ling
Yaochun
Y
Zhang
Ka-Yun
KY
Ng
Eng-Hui
EH
Chew
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D003720:Densitometry / Q000379:methods; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D013997:Time Factors; D015533:Transcriptional Activation; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C102487:pachymic acid