期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：5
页码：1428-1433
DOI：10.1073/pnas.1412592112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite the integral role of cell mechanics, efforts to target mechanics for drug development have lagged. Here, we present an approach to identifying small molecules capable of modulating mechanics. We characterize 4-hydroxyacetophenone (4-HAP), isolated as a breakdown product of a hit from our pilot screen of over 22,000 compounds. We show that 4-HAP specifically alters the localization of the mechanoenzyme myosin II, increasing the stiffness of cells. The effect of 4-HAP on myosin II, whose specificity we have defined, occurs across phylogeny. In particular, we have demonstrated 4-HAP's ability to convert the mechanical profile of metastasis-derived pancreatic cancer cells toward a normal WT-like state. Invasion and migration of these cells, which are hallmarks of the invasive capacity of malignant lesions, are decreased by 4-HAP. 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.
关键词：mechanical modulator ; 3,4-dichloroaniline ; 4-hydroxyacetophenone ; myosin II ; pancreatic cancer
