@article {941, title = {The tumor invasion inhibitor dihydromotuporamine C activates RHO, remodels stress fibers and focal adhesions, and stimulates sodium-proton exchange}, journal = {Cancer Research}, volume = {64}, number = {4}, year = {2004}, note = {ISI Document Delivery No.: 778MKTimes Cited: 23Cited Reference Count: 45}, month = {Feb}, pages = {1468-1474}, type = {Article}, 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.}, keywords = {ANGIOGENESIS, CANCER, CELL-MIGRATION, FARNESYLTRANSFERASE INHIBITORS, GROWTH, GTP-BINDING PROTEIN, GTPASES, KINASE, MEMBRANE PROTRUSION, PROGRESSION}, isbn = {0008-5472}, url = {://000189245200037}, author = {McHardy, L. M. and Sinotte, R. and Troussard, A. and Sheldon, C. and Church, J. and Williams, D. E. and Andersen, R. J. and Dedhar, S. and Roberge, M. and Roskelley, C. D.} }