4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis

Darren S. Bryan, Melinda Stack, Katarzyna Krysztofiak, Urszula Cichoń, Dustin G. 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)22423-22429
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number36
DOIs
StatePublished - Sep 8 2020

Keywords

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

ASJC Scopus subject areas

  • General

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    Bryan, D. S., Stack, M., Krysztofiak, K., Cichoń, U., Thomas, D. G., Surcel, A., Schiffhauer, E. S., Beckett, M. A., Khodarev, N. N., Xue, L., Poli, E. C., Pearson, A. T., Posner, M. C., Robinson, D. N., Rock, R. S., & Weichselbaum, R. R. (2020). 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis. Proceedings of the National Academy of Sciences of the United States of America, 117(36), 22423-22429. https://doi.org/10.1073/pnas.2014639117