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The tumor invasion inhibitor dihydromotuporamine C activates RHO, remodels stress fibers and focal adhesions, and stimulates sodium-proton exchange

TitleThe tumor invasion inhibitor dihydromotuporamine C activates RHO, remodels stress fibers and focal adhesions, and stimulates sodium-proton exchange
Publication TypeJournal Article
Year of Publication2004
AuthorsMcHardy, LM, Sinotte, R, Troussard, A, Sheldon, C, Church, J, Williams, DE, Andersen, RJ, Dedhar, S, Roberge, M, Roskelley, CD
JournalCancer Research
Volume64
Pagination1468-1474
Date PublishedFeb
Type of ArticleArticle
ISBN Number0008-5472
KeywordsANGIOGENESIS, CANCER, CELL-MIGRATION, FARNESYLTRANSFERASE INHIBITORS, GROWTH, GTP-BINDING PROTEIN, GTPASES, KINASE, MEMBRANE PROTRUSION, PROGRESSION
Abstract

The motuporamines are macrocyclic alkaloids that inhibit tumor cell invasion by an, as yet, unknown mechanism. A structure-activity study recently identified dihydromotuporamine C (dhMotC) as a highly active and readily synthesized analogue. Here, we show that dhMotC causes subtle cytoskeletal alterations in highly invasive MDA231 breast tumor cells that include an increase in the thickness and number of cytoplasmic actin stress fibers. Experiments with serum-starved Swiss 3T3 fibroblasts showed that micromolar concentrations of dhMotC that inhibit tumor cell invasion induce the formation of new stress fibers and large focal adhesion complexes that are dispersed around the entire cell periphery. dhMotC treatment of Swiss 3T3 cells also initiates a strong, long-lived activation of the small GTP-binding protein Rho, and it stimulates Rho kinase-dependent sodium-proton exchanger activity. Liposome-mediated cell loading of C3 exoenzyme prevents dhMotC-mediated Rho activation and stress fiber formation in 3T3 cells. C3 exoenzyme loading also reestablishes elongated MDA231 breast tumor cell invasion in the presence of dhMotC. Taken together, these results indicate that the ability to activate Rho is one important determinant of the anti-invasive activity of dhMotC.

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