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Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1428-33. doi: 10.1073/pnas.1412592112. Epub 2015 Jan 20.

Pharmacological activation of myosin II paralogs to correct cell mechanics defects.

Author information

1
Departments of Cell Biology, asurcel1@jhmi.edu dnr@jhmi.edu.
2
Departments of Cell Biology.
3
Pathology, and.
4
Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
5
Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637.
6
Departments of Cell Biology, Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218; and asurcel1@jhmi.edu dnr@jhmi.edu.

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.

KEYWORDS:

3,4-dichloroaniline; 4-hydroxyacetophenone; mechanical modulator; myosin II; pancreatic cancer

PMID:
25605895
PMCID:
PMC4321244
DOI:
10.1073/pnas.1412592112
[Indexed for MEDLINE]
Free PMC Article

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