Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo
Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo
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DOI：
10.1158/0008-5472.can-08-1296
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
--
作者：
Vogler, Meike;Walczak, Henning;Fulda, Simone
对细胞凋亡的抵抗是胰腺癌的标志，胰腺癌是癌症死亡的主要原因。因此，需要新的策略来靶向细胞凋亡抗性。在这里，我们报告说，X连锁的细胞凋亡抑制剂（XIAP）抑制和肿瘤坏死因子相关的凋亡诱导配体（TRAIL）的组合是一种有效的方法，触发细胞凋亡，尽管Bcl-2过表达和抑制胰腺癌生长在体外和体内。通过RNA干扰敲低XIAP与TRAIL协同诱导胰腺癌细胞中的半胱天冬酶活化、线粒体膜电位损失、细胞色素c释放和凋亡。线粒体膜电位的丧失和细胞色素c的释放被广泛的caspase-3选择性caspase抑制剂和RNA干扰介导的caspase-3沉默广泛抑制，表明XIAP抑制以caspase-3依赖性方式增强TRAIL诱导的线粒体损伤。XIAP抑制与TRAIL组合甚至通过将依赖于线粒体对死亡受体途径的贡献的11型细胞转化为I型细胞来打破Bcl-2施加的抗性，在I型细胞中，TRAIL诱导的半胱天冬酶-3和半胱天冬酶-9的活化和凋亡的进行与高Bcl-2水平无关。最重要的是，XIAP抑制增强了体内胰腺癌的两个临床前模型中TRAIL诱导的抗肿瘤活性。在鸡绒毛尿囊膜模型中，XIAP抑制显著增强TRAIL介导的细胞凋亡和肿瘤生长抑制。在异种移植荷瘤小鼠的肿瘤消退模型中，XIAP抑制与TRAIL协同作用，甚至导致已建立的胰腺癌消退。因此，XIAP抑制加TRAIL的这种组合是克服胰腺癌细胞凋亡抗性的有希望的策略，值得进一步研究。
Resistance to apoptosis is a hallmark of pancreatic cancer, a leading cause of cancer deaths. Therefore, novel strategies are required to target apoptosis resistance. Here, we report that the combination of X-linked inhibitor of apoptosis (XIAP) inhibition and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective approach to trigger apoptosis despite Bcl-2 overexpression and to suppress pancreatic cancer growth in vitro and in vivo. Knockdown of XIAP by RNA interference cooperates with TRAIL to induce caspase activation, loss of mitochondrial membrane potential, cytochrome c release, and apoptosis in pancreatic carcinoma cells. Loss of mitochondrial membrane potential and cytochrome c release are extensively inhibited by a broad range or caspase-3 selective caspase inhibitor and by RNAi-mediated silencing of caspase-3, indicating that XIAP inhibition enhances TRAIL-induced mitochondrial damage in a caspase-3-dependent manner. XIAP inhibition combined with TRAIL even breaks Bcl-2-imposed resistance by converting type 11 cells that depend on the mitochondrial contribution to the death receptor pathway to type I cells in which TRAIL-induced activation of caspase-3 and caspase-9 and apoptosis proceeds irrespective of high Bcl-2 levels. Most importantly, XIAP inhibition potentiates TRAIL-induced antitumor activity in two preclinical models of pancreatic cancer in vivo. In the chicken chorioallantoic membrane model, XIAP inhibition significantly enhances TRAIL-mediated apoptosis and suppression of tumor growth. In a tumor regression model in xenograft-bearing mice, XIAP inhibition acts in concert with TRAIL to cause even regression of established pancreatic carcinoma. Thus, this combination of XIAP inhibition plus TRAIL is a promising strategy to overcome apoptosis resistance of pancreatic cancer that warrants further investigation.