Pharmacological activation of myosin ii paralogs to correct cell mechanics defects

Alexandra Surcel, Win Pin Ng, Hoku West-Foyle, Qingfeng Zhu, Yixin Ren, Lindsay B. Avery, Agata K. Krenc, David J Meyers, Ronald S. Rock, Robert A Anders, Caren L Meyers, Douglas Robinson

Research output: Contribution to journalArticle

Abstract

Current approaches to cancer treatment focus on targeting signal transduction pathways. Here, we develop an alternative system for targeting cell mechanics for the discovery of novel therapeutics. We designed a live-cell, high-throughput chemical screen to identify mechanical modulators. We characterized 4-hydroxyacetophenone (4-HAP), which enhances the cortical localization of the mechanoenzyme myosin II, independent of myosin heavy-chain phosphorylation, thus increasing cellular cortical tension. To shift cell mechanics, 4-HAP requires myosin II, including its full power stroke, specifically activating human myosin IIB (MYH10) and human myosin IIC (MYH14), but not human myosin IIA (MYH9). We further demonstrated that invasive pancreatic cancer cells are more deformable than normal pancreatic ductal epithelial cells, a mechanical profile that was partially corrected with 4-HAP, which also decreased the invasion and migration of these cancer cells. Overall, 4-HAP modifies nonmuscle myosin II-based cell mechanics across phylogeny and disease states and provides proof of concept that cell mechanics offer a rich drug target space, allowing for possible corrective modulation of tumor cell behavior.

Original languageEnglish (US)
Pages (from-to)1428-1433
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number5
DOIs
StatePublished - Feb 3 2015

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Keywords

  • 3,4-dichloroaniline
  • 4-hydroxyacetophenone
  • Mechanical modulator
  • Myosin ii
  • Pancreatic cancer

ASJC Scopus subject areas

  • General

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