胰腺导管腺癌属于最常见的癌症，也是预后最差的肿瘤。在这里，我们在药理学上靶向线粒体钾通道，即线粒体 Kv1.3，并研究了鞘脂和突变的克尔斯滕大鼠肉瘤病毒 (KRAS) 在 Kv1.3 介导的细胞死亡中的作用。我们证明，使用 Kv1.3 抑制剂 PAPTP 抑制 Kv1.3 会导致膜和/或与线粒体相关的膜中的鞘氨醇和超氧化物增加，而 KRAS 突变会增强这种增加。 sh-RNA 介导的 Kv1.3 下调可防止 PAPTP 对鞘氨醇和线粒体超氧化物形成以及细胞死亡的影响。 PAPTP 在人胰腺癌细胞中诱导鞘氨醇是通过 1-磷酸鞘氨醇磷酸酶的激活介导的，并被 1-磷酸鞘氨醇磷酸酶抑制剂阻止。鞘氨醇与心磷脂的结合引发分离线粒体的快速去极化，而心磷脂的结合可通过添加外源心磷脂来中和。用 PAPTP 联合 ABC294640（一种鞘氨醇激酶阻断剂）治疗携带突变 KRAS 的转移性胰腺癌表明了这些发现的重要性。这种治疗导致体外鞘氨醇的形成增加和胰腺癌细胞死亡，最重要的是，延长了患有转移性胰腺癌的小鼠的体内存活时间。关键信息：胰腺导管腺癌（PDAC）是一种常见肿瘤，预后不良。线粒体 Kv1.3 离子通道阻滞剂诱导线粒体鞘氨醇。鞘氨醇与心磷脂结合，从而介导线粒体去极化。鞘氨醇是由 PAPTP 介导的 S1P 磷酸酶激活形成的。抑制鞘氨醇消耗会放大体内 PAPTP 对 PDAC 的影响。© 2024。作者。

Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine. Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization. Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase. Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo.© 2024. The Author(s).