Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling.
Metastasis is one of the most important factors related to breast cancer therapeutic efficacy. Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, we first observed that ursolic acid exerted a dose- and time-dependent inhibitory effect on the migration and invasion of highly metastatic breast MDAMB231 cells at non-cytotoxic concentrations. This effect was associated with reduced activities of metalloproteinase-2 (MMP-2) and u-PA, which correlated with enhanced expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFkappaB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFkappaB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer.
Yeh
Chi-Tai
CT
National Institute of Cancer Research, National Health Research Institutes, Miaoli County, Taiwan.
Wu
Chi-Hao
CH
Yen
Gow-Chin
GC
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
D000972:Antineoplastic Agents, Phytogenic; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C546842:MTOR protein, human