Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.

中文翻译：

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前列腺素E2及其受体EP2触发信号传导，从而促进YAP介导的细胞竞争。

细胞竞争是一个生物学过程，通过该过程，不适合的细胞被排除在“细胞社会”之外。我们先前显示，当被“正常” MDCK细胞围绕时，表达的组成性活性YAP的培养的哺乳动物上皮Madin-Darby犬肾（MDCK）细胞被根尖挤压消除。但是，尚不清楚消除活跃的表达YAP的细胞的分子机制。在这里，我们使用高通量化合物筛选来确定环氧合酶2（COX-2）是触发细胞竞争的关键分子。我们的工作表明，COX-2介导的PGE2分泌与异常和附近正常细胞的受体EP2结合。EP2的这种参与通过腺苷酸环化酶-环AMP-PKA途径触发下游信号传导，在存在活性YAP的情况下，诱导E-钙粘着蛋白内在化，导致根尖挤压。因此，COX-2诱导的PGE2对异常细胞和周围正常细胞都发出警告信号，以驱动细胞竞争。