The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin Article

Bargagna-Mohan, P, Hamza, A, Kim, YE et al. (2007). The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin . CHEMISTRY & BIOLOGY, 14(6), 623-634. 10.1016/j.chembiol.2007.04.010

cited authors

  • Bargagna-Mohan, P; Hamza, A; Kim, YE; Khuan (Abby) Ho, Y; Mor-Vaknin, N; Wendschlag, N; Liu, J; Evans, RM; Markovitz, DM; Zhan, CG; Kim, KB; Mohan, R

authors

abstract

  • The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved α-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases. © 2007 Elsevier Ltd. All rights reserved.

publication date

  • June 25, 2007

published in

Digital Object Identifier (DOI)

start page

  • 623

end page

  • 634

volume

  • 14

issue

  • 6