Migrastatin analogues target fascin to block tumour metastasis

Abstract

Analogues of the natural product migrastatin are potent inhibitors of tumour cell migration and metastasis. In this study, Lin Chen et al. elucidate the mechanism involved and show that these migrastatin analogues target and inhibit the activity of the actin bundling protein, fascin. These results suggest that actin cytoskeletal proteins, such as fascin, may present new molecular targets for cancer treatment. Analogues of migrastatin — a natural product secreted by Streptomyces — are potent inhibitors of tumour cell migration and metastasis. Here, the underlying mechanism is elucidated: these migrastatin analogues target and inhibit the activity of the actin-bundling protein fascin. Hence proteins such as fascin might present new molecular targets for cancer treatments. Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces1,2, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis3,4,5,6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.