2. Academic Validation
  3. 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis

4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis

  • Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22423-22429. doi: 10.1073/pnas.2014639117.
Darren S Bryan 1,  Melinda Stack 1,  Katarzyna Krysztofiak 2 3,  Urszula Cichoń 2 4,  Dustin G Thomas 5,  Alexandra Surcel 5,  Eric S Schiffhauer 5,  Michael A Beckett 6 7,  Nikolai N Khodarev 6 7,  Lai Xue 1,  Elizabeth C Poli 1,  Alexander T Pearson 8,  Mitchell C Posner 1,  Douglas N Robinson 5,  Ronald S Rock 9,  Ralph R Weichselbaum 10 7
Affiliations

Affiliations

  • 1 Department of Surgery, The University of Chicago, Chicago, IL 60637.
  • 2 Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637.
  • 3 Faculty of Biology, University of Warsaw, 00-927 Warsaw, Poland.
  • 4 Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 31-007 Kraków, Poland.
  • 5 Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
  • 6 Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637.
  • 7 The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637.
  • 8 Department of Medicine, The University of Chicago, Chicago, IL 60637.
  • 9 Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637; rrock@uchicago.edu rrw@radonc.uchicago.edu.
  • 10 Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637; rrock@uchicago.edu rrw@radonc.uchicago.edu.
PMID: 32848073 DOI: 10.1073/pnas.2014639117
Abstract

Metastases are the cause of the vast majority of Cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the Cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon Cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon Cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of Myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.

Keywords

4-hydroxyacetophenone; colorectal cancer; ex vivo motility; metastasis; nonmuscle myosin 2C.

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