PDF(Pubmed)
Abstract：
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.
摘要：
胰腺导管腺癌属于最常见的癌症，还有预后最差的肿瘤。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Kirsten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导致膜和/或与线粒体相关的膜中鞘氨醇和超氧化物的增加，KRAS突变增强。sh-RNA介导的Kv1.3下调可阻止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在人胰腺癌细胞中鞘氨醇的诱导是由鞘氨醇-1-磷酸磷酸酶的激活介导的，并由鞘氨醇-1-磷酸磷酸酶的抑制剂阻止。鞘氨醇与心磷脂的结合触发了分离的线粒体的快速去极化，通过添加外源性心磷脂中和。这些发现的重要性通过用PAPTP与鞘氨醇激酶阻断剂ABC294640联合治疗突变的KRAS转移的胰腺癌来表明。这种治疗导致鞘氨醇的形成增加和胰腺癌细胞的体外死亡，最重要的是,延长受转移性胰腺癌攻击的小鼠的体内生存期。关键信息：胰腺导管腺癌（PDAC）是一种常见的预后不良的肿瘤。线粒体Kv1.3离子通道阻断剂诱导线粒体鞘氨醇。鞘氨醇结合心磷脂,从而介导线粒体去极化。鞘氨醇由PAPTP介导的S1P-磷酸酶活化形成。鞘氨醇消耗的抑制增强了体内PAPTP对PDAC的作用。
