XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis.
XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis.
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DOI：
10.1038/cddis.2014.534
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发表时间：
2014-12-11
影响因子：
9
通讯作者：
Wajant H
中科院分区：
文献类型：
--
作者：
Ehrenschwender M;Bittner S;Seibold K;Wajant H
10-20% 的结直肠癌 (CRC) 中发现致癌 PIK3CA 基因突变，且与不良预后相关。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 和激动性 TRAIL 死亡受体抗体作为有前景的抗肿瘤治疗药物出现，但迄今为止未能证明其在临床环境中的能力，因为特别是原发性肿瘤表现出高 TRAIL 耐药率。在我们的研究中，我们研究了具有突变 PIK3CA (PIK3CA-mut) 基因的 CRC 细胞中 TRAIL 抗性的分子机制。我们发现，尽管可以注意到 TRAIL 与 PI3K、Akt 或细胞周期蛋白依赖性激酶 (CDK) 抑制剂的协同作用，但在 PIK3CA-mut 保护的 HCT116 细胞中，对组成型活性磷脂酰肌醇 3 激酶 (PI3K)/Akt 信号通路的抑制仅部分克服了 TRAIL 耐药性。与此形成鲜明对比的是，在用硼替佐米和 MG132 等蛋白酶体抑制剂处理的 HCT116 PIK3CA-mut 细胞中，TRAIL 触发了全面的细胞死亡诱导。在分子水平上，HCT116 PIK3CA-mut 细胞对 TRAIL 的抵抗通过受损的 caspase-3 激活反映出来，我们为 E3 连接酶 X 连锁凋亡蛋白抑制剂 (XIAP) 的重要参与提供了证据。干扰 XIAP 活性和/或表达的药物，例如第二种线粒体衍生的 caspase 模拟物 BV6 和光神霉素-A，完全恢复了 PIK3CA-mut 保护的 HCT116 细胞中的 TRAIL 敏感性，不依赖于功能性线粒体细胞死亡途径。重要的是，蛋白酶体抑制剂和 XIAP 靶向剂还使其他具有突变 PIK3CA 的 CRC 细胞系对 TRAIL 诱导的细胞死亡敏感。总之，我们的数据表明，蛋白酶体或 XIAP 靶向药物提供了一种新的治疗方法来克服 PIK3CA 突变 CRC 中的 TRAIL 耐药性。
Mutations in the oncogenic PIK3CA gene are found in 10–20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.