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Departments of ¹ Biochemistry and Molecular Biology, ² Chemistry and Earth and Ocean Sciences, and ³ Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Michel Roberge, Department of Biochemistry and Molecular Biology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: 604-822-2304; Fax: 604-822-5227. E-mail: michelr{at}interchange.ubc.ca

Strongylophorine-26, a new meroditerpenoid, was recently identified as an inhibitor of cancer cell invasion. This study was undertaken to characterize its mechanism of action. We find that strongylophorine-26 inhibits the motility of MDA-MB-231 breast carcinoma cells on a plastic surface. Upon addition of strongylophorine-26, rapid cell contraction and depolarization occurred, followed by spreading and flattening of the entire cell. Treated cells exhibited increased membrane ruffling throughout and extended lamellipodia in all directions. Strongylophorine-26 induced a decrease in actin stress fibers, a dramatic increase in the size and number of focal adhesions, and the appearance of a dense meshwork of actin filaments around the cell periphery. Strongylophorine-26 caused a transient activation of the small GTPase Rho and treatment with the Rho inhibitor C3 exoenzyme abrogated the anti-invasive activity of strongylophorine-26. These effects are distinct from those of many motility and angiogenesis inhibitors that seem to act by a common mechanism involving the induction of actin stress fibers. This difference in mechanism of action sets strongylophorine-26 apart as an experimental anticancer agent and indicates that pharmacologic inhibition of cell migration may be achieved by mechanisms not involving the stabilization of actin stress fibers.

Key Words: actin stress fibers • angiogenesis • invasion • motility • rho

Grant support: National Cancer Institute of Canada (M. Roberge and R.J. Andersen), the Canadian Breast Cancer Research Alliance (C.D. Roskelley) and the Michael Smith Foundation for Health Research (M. Roberge, R.J. Andersen, and C.D. Roskelley).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ L.M. McHardy, unpublished observations.

Received 11/19/04; revised 1/24/05; accepted 3/ 2/05.