4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis
Darren S. Bryan, Melinda E. Stack, Katarzyna Krysztofiak, Urszula Cichoń, Dustin Thomas, Alexandra Surcel, Eric S. Schiffhauer, Michael A. Beckett, Nikolai N. Khodarev, Lai Xue, Elizabeth C. Poli, Alexander T. Pearson, Mitchell C. Posner, Douglas N. Robinson, Ronald S. Rock, Ralph R. Weichselbaum
Abstract
Significance There is a pressing need for new approaches to combat metastatic disease. We demonstrate, here, a strategy that targets and activates the molecular machines that control cell shape in cell division, wound healing, immune surveillance, embryonic development, and cancer metastasis. Cells control their shape by remodeling their cytoskeletal actin filaments, microtubules, and intermediate filaments, while cytoskeletal motor proteins, such as the myosins generate forces that can produce local contractions. By targeting and activating NM2C directly, we interfere with cytoskeletal plasticity. We demonstrate the effectiveness of this activation strategy in vitro and in vivo and provide a molecular mechanism for our measured increase in cell stiffness. Our strategy can be integrated readily with existing approaches to combat aggressive cancers.