Strongylophorine-26, a Rho-dependent inhibitor of tumor cell invasion that reduces actin stress fibers and induces nonpolarized lamellipodial extensions.
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.
McHardy
Lianne M
LM
Department of Biochemistry and Molecular Biology, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3, USA.
Warabi
Kaoru
K
Andersen
Raymond J
RJ
Roskelley
Calvin D
CD
Roberge
Michel
M
D036002:ADP Ribose Transferases / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D001905:Botulinum Toxins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D011554:Pseudopodia / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D000199:Actins; D004224:Diterpenes; C491871:strongylophorine-26; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020741:rho GTP-Binding Proteins