Synthetic triterpenoids target the Arp2/3 complex and inhibit branched actin polymerization.
Synthetic triterpenoids are anti-tumor agents that affect numerous cellular functions including apoptosis and growth inhibition. Here, we used mass spectrometric and protein array approaches and uncovered that triterpenoids associate with proteins of the actin cytoskeleton, including actin-related protein 3 (Arp3). Arp3, a subunit of the Arp2/3 complex, is involved in branched actin polymerization and the formation of lamellipodia. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-Im and CDDO-Me were observed to 1) inhibit the localization of Arp3 and actin at the leading edge of cells, 2) abrogate cell polarity, and 3) inhibit Arp2/3-dependent branched actin polymerization. We confirmed our drug effects with siRNA targeting of Arp3 and observed a decrease in Rat2 cell migration. Taken together, our data suggest that synthetic triterpenoids target Arp3 and branched actin polymerization to inhibit cell migration.
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Ciric
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Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Shilton
Brian H
BH
Di Guglielmo
Gianni M
GM
D051376:Actin-Related Protein 2-3 Complex / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000199:Actins / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D051381:Rats; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D007093:Imidazoles; D014315:Triterpenes; D009828:Oleanolic Acid; C445068:bardoxolone methyl