abstract Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium–hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. Significance: NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a “proton sink” for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth. See related commentary by Ward and DeNicola, [p. 768][1] . This article is highlighted in the In This Issue feature, [p. 747][2] [1]: /lookup/volpage/10/768?iss=6 [2]: /lookup/volpage/10/747?iss=6

中文翻译：

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NHE7 的高尔基酸化调节胰腺癌细胞中的细胞溶质 pH 稳态。

摘要 癌细胞重新编程其新陈代谢以满足更高的能量需求并有利于糖酵解产生能量。这种糖酵解通量的增加支持增殖，但也产生氢离子形式的酸，必须将其从细胞质中消除以维持与转化相关的碱性细胞内 pH (pHi)。为了应对酸的产生，肿瘤细胞采用离子转运系统，包括钠氢交换剂 (NHE) 家族。在这里，我们将 NHE7 鉴定为胰腺导管腺癌 (PDAC) 中 pHi 的新型调节剂。我们确定 NHE7 抑制导致高尔基体碱化，导致细胞溶质酸的积累，主要通过肌动蛋白的失调降低肿瘤细胞的适应性。重要的是，体内 NHE7 敲低导致肿瘤生长的消除。这些结果确定高尔基酸化是控制 pHi 的一种机制，并指出调节 pHi 作为 PDAC 中可能的治疗脆弱性。意义：NHE7 通过高尔基酸化调节胞浆 pH，这表明高尔基是代谢酸的“质子汇”。通过 NHE7 抑制破坏细胞溶质 pH 稳态会损害 PDAC 细胞活力和肿瘤生长。见 Ward 和 DeNicola 的相关评论，[p. 768][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/768?iss=6 [2]:/lookup/volpage/10/747?iss=6 这表明高尔基体是代谢酸的“质子汇”。通过 NHE7 抑制破坏细胞溶质 pH 稳态会损害 PDAC 细胞活力和肿瘤生长。见 Ward 和 DeNicola 的相关评论，[p. 768][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/768?iss=6 [2]:/lookup/volpage/10/747?iss=6 这表明高尔基体是代谢酸的“质子汇”。通过 NHE7 抑制破坏细胞溶质 pH 稳态会损害 PDAC 细胞活力和肿瘤生长。见 Ward 和 DeNicola 的相关评论，[p. 768][1]。本文在 In This Issue 功能中突出显示，[p. 747][2] [1]:/lookup/volpage/10/768?iss=6 [2]:/lookup/volpage/10/747?iss=6