Inhibition of matrix metalloproteinase-2 by halofuginone is mediated by the Egr1 transcription factor

Abstract

Halofuginone, a low-molecular-weight quinazolinone alkaloid that inhibits collagen α1(I), has been shown to suppress cancer growth, metastasis, and angiogenesis. These activities were attributed in part to the inhibition of matrix metalloproteinase-2 (MMP-2). The present study was carried out to explore the molecular mechanism underlying this effect. We found a marked (50%) inhibition in MMP-2 gelatinolytic activity in human breast cancer MDA-MB-435 cells pretreated with as little as 50 ng/ml of halofuginone, a concentration that markedly inhibited their invasive and proliferative capacities. We further show that both early growth response 1 (Egr-1) and Nab-2 (corepressor of Egr1 activation) are upregulated by halofuginone in a dose-dependent and time-dependent (up to 5 h) manner. Using MMP-2 reporter gene and chromatin immunoprecipitation analyses, we found that Egr-1 binds to the MMP-2 promoter and inhibits its activity. Altogether, our results identify the downstream elements (Egr-1, Nab-2, and MMP-2) by which halofuginone exerts its antitumoral effect, thereby advancing its potential therapeutic application as an anticancer drug.© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.