文章基本信息

标题：ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition
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作者：Takeshi Maruyama ; Ayana Sasaki ; Sayuri Iijima 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：7
页码：1-27
DOI：10.1016/j.isci.2020.101327
语种：English
出版社：Elsevier
摘要：SummaryPrevious studies have revealed that, at the initial step of carcinogenesis, transformed cells are often eliminated from epithelia via cell competition with the surrounding normal cells. In this study, we performed cell competition-based high-throughput screening for chemical compounds using cultured epithelial cells and confocal microscopy. PLX4720 was identified as a hit compound that promoted apical extrusion of RasV12-transformed cells surrounded by normal epithelial cells. Knockdown/knockout of ZAK, a target of PLX4720, substantially enhanced the apical elimination of RasV12 cellsin vitroandin vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cellsin vivoand suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competition-promoting chemical drug facilitates apical elimination of transformed cellsin vivo, providing a new dimension in cancer preventive medicine.Graphical AbstractDisplay OmittedHighlights•A cell competition-based high-throughput screen identifies chemical enhancers•PLX4720 enhances the apical elimination of RasV12 cells via ZAK inhibition•ZAK negatively modulates cell competition regulators•PLX4720 treatment promotes apical elimination of RasV12 cellsin vivoChemistry; Biological Sciences; Cancer