Epithelial–mesenchymal transition (EMT) induces tumor-initiating cells (TIC), which account for tumor recurrence, metastasis, and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as a promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EMT process and inhibit TIC generation, as shown by a reduced formation of mammospheres and decreased cell motility. As an underlying mechanism, V-ATPase inhibition by Archazolid A disturbs the turnover of E-cadherin: Archazolid abrogates E-cadherin loss during EMT by interfering with its internalization and recycling. Our study elucidates V-ATPase as essential player in EMT by regulating E-cadherin turnover. Archazolid A is suggested as a promising therapeutic agent to block EMT and the generation of TICs. Mol Cancer Ther; 16(11); 2329–39. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

中文翻译：

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Archazolid A对V-ATPase的抑制作用：一种抑制EMT的新策略

上皮-间质转化（EMT）诱导肿瘤起始细胞（TIC），这解释了肿瘤的复发，转移和治疗耐药性。干扰EMT的策略很少见，但迫切需要改善癌症治疗。通过使用粘细菌天然化合物Archazolid A作为工具，我们阐明了V-ATPase（一种调节溶酶体酸化的多聚质子泵）作为EMT中的关键角色，并确定Archazolid A对V-ATPase的抑制是一种有前途的策略阻止EMT。如通过减少球囊的形成和降低细胞运动性所表明的，阿卡唑利德A的基因敲除和V-ATPase的药理抑制作用会干扰EMT过程并抑制TIC的产生。作为一种潜在的机制，Archazolid A对V-ATPase的抑制作用会干扰E-cadherin的更新：Archazolid通过干扰其内在化和回收利用来消除EMT中的E-钙黏着蛋白损失。我们的研究阐明了V-ATPase是EMT中必不可少的参与者，它通过调节E-钙粘蛋白的转化来实现。建议将阿奇唑利德A用作阻止EMT和TIC产生的有前途的治疗剂。分子癌疗法；16（11）; 2329–39。©2017 AACR。本文在本期要点[p。2327] [1] [1]：/ lookup / volpage / 16/2327？iss = 11