title: 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.
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Ruth
authors.initials: R
authors.lastname: Atzmon
authors.forename: Adi
authors.initials: A
authors.lastname: Nagler
authors.forename: Avichai
authors.initials: A
authors.lastname: Shimoni
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D052999:Quinazolinones / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D061965:Matrix Metalloproteinase Inhibitors; C491000:NAB2 protein, human; D010880:Piperidines; D052999:Quinazolinones; D012097:Repressor Proteins; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2; C010176:halofuginone