ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition
ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition
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DOI：
10.1016/j.isci.2020.101327
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发表时间：
2020-07-24
期刊：
影响因子：
5.8
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Maruyama, Takeshi;Sasaki, Ayana;Fujita, Yasuyuki
先前的研究表明，在癌变的最初阶段，转化的细胞通常通过与周围正常细胞的细胞竞争从上皮细胞中消除。在这项研究中，我们使用培养的上皮细胞和共聚焦显微镜进行了基于细胞竞争的高通量化合物筛选。PLX4720被鉴定为一种HIT化合物，它促进RasV12转化的细胞被正常上皮细胞包围的顶端挤出。PLX4720的靶点Zak的敲除/敲除在体外和体内都显著增强了RasV12细胞的顶端消除。ZAK负性调节多个细胞竞争调节因子的积累或激活。此外，PLX4720治疗促进了体内RasV12转化细胞的顶端消除，并抑制了潜在的癌前肿瘤的形成。这是第一个证明促进细胞竞争的化学药物促进体内转化细胞根尖消除的报道，为癌症预防医学提供了一个新的维度。
Previous studies have revealed that, at the initial step of carcinogenesis, trans-formed 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 pro-moted 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 cells in vitro and in vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cells in vivo and suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competi-tion-promoting chemical drug facilitates apical elimination of transformed cells in vivo, providing a new dimension in cancer preventive medicine.