Synthetic Triterpenoids Target the Arp2/3 Complex and Inhibit Branched Actin Polymerization

Authors

Ciric To, The University of Western Ontario
Brian H. Shilton, The University of Western Ontario
Gianni M. Di Guglielmo, The University of Western Ontario

Document Type

Article

Publication Date

9-3-2010

Journal

The Journal of Biological Chemistry

Volume

285

Issue

36

First Page

27944

Last Page

27957

URL with Digital Object Identifier

http://dx.doi.org/10.1074/jbc.M110.103036

Abstract

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. 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.