Zoledronic Acid Reverses the Epithelial-Mesenchymal Transition and Inhibits Self-Renewal of Breast Cancer Cells through Inactivation of Nuclear Factor kappa B
Menée in vitro, cette étude met en évidence un mécanisme par lequel, en inactivant la signalisation NFκB, l'acide zolédronique inhibe la capacité d'auto-renouvellement des cellules de cancer du sein
Zoledronic acid (ZA), a third generation bisphosphonate, has been shown to reduce cell migration, invasion, and metastasis. However, the effects of ZA on the epithelial-mesenchymal transition (EMT), a cellular process essential to the metastatic cascade, remain unclear. Therefore, the effects of ZA on EMT, using triple negative breast cancer cells (TNBC) as a model system, were examined in greater detail. ZA treatment decreased expression of mesenchymal markers N-cadherin, Twist and Snail, and subsequently upregulated expression of E-cadherin. ZA also inhibited cell viability, induced cell cycle arrest and decreased the proliferative capacity of TNBC, suggesting that ZA inhibits viability through reduction of cell proliferation. As EMT has been linked to acquisition of a self-renewal phenotype, the effects of ZA on self-renewal in TNBC were also studied. Treatment with ZA decreased expression of self-renewal proteins BMI-1 and Oct-4, and both prevented and eliminated mammosphere formation. To understand the mechanism of these results, the effect of ZA on established EMT regulator NFκB was investigated. ZA inhibited phosphorylation of RelA, the active subunit of NFκB, at serine 536 and modulated RelA subcellular localization. Treatment with ZA reduced RelA binding to the Twist promoter, providing a direct link between inactivation of NFκB signaling and loss of EMT transcription factor gene expression. Binding of Twist to the BMI-1 promoter was also decreased, correlating modulation of EMT to decreased self-renewal. Based on these results, it is proposed that, through inactivation of NFκB, ZA reverses EMT, which leads to a decrease in self-renewal.
http://mct.aacrjournals.org/content/early/2013/04/25/1535-7163.MCT-12-0304.abstract