HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells.
HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells.
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DOI：
10.1158/1541-7786.mcr-15-0448
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Brody JR
中科院分区：
文献类型：
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作者：
Romeo C;Weber MC;Zarei M;DeCicco D;Chand SN;Lobo AD;Winter JM;Sawicki JA;Sachs JN;Meisner-Kober N;Yeo CJ;Vadigepalli R;Tykocinski ML;Brody JR
胰腺导管腺癌（PDA）是最致命的癌症之一，部分原因是对传统疗法和靶向疗法的耐药性。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 通过与细胞表面死亡受体（DR4 和 DR5）结合直接诱导细胞凋亡，并已被探索作为癌症治疗的分子靶点。然而，重组 TRAIL 和 DR 靶向药物的临床试验未能显示出总体积极的结果。在此，我们确定了一种由 Hu 抗原 R（HuR，ELAV1）控制的新型 TRAIL 抗性机制，Hu 抗原 R 是一种在 PDA 细胞中丰富且有功能的应激反应蛋白。 TRAIL 敏感的 PDA 细胞系中外源 HuR 过表达会增加 TRAIL 抗性，而通过 siRNA 寡核苷酸转染沉默 TRAIL 抗性 PDA 细胞中的 HuR 会降低 TRAIL 抗性。 PDA 细胞暴露于可溶性 TRAIL 会诱导 HuR 从细胞核易位到细胞质。此外，已证明 HuR 与 DR4 mRNA 的 3'-非翻译区 (UTR) 相互作用。用 MS-444（诺华公司）（一种成熟的 HuR 小分子抑制剂）预处理 PDA 细胞，显着增加了 DR4 和 DR5 细胞表面水平并增强了 TRAIL 敏感性，进一步验证了 HuR 在影响 TRAIL 抗凋亡中的作用。 NanoString™ 对 TRAIL 暴露的 PDA 细胞的转录组进行分析，发现 HuR 介导的整体抗凋亡过程增加。总而言之，这些数据扩展了 HuR 作为 TRAIL 诱导细胞凋亡的关键调节因子的作用。一种重要的新 HuR 介导的 TRAIL 耐药机制的发现表明，肿瘤靶向 HuR 抑制增加了对基于 TRAIL 的治疗的敏感性，并支持将其重新评估为 PDA 患者的有效治疗方法。
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3′-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR’s role in affecting TRAIL apoptotic-resistance. NanoString™ analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in anti-apoptotic processes. Taken together, these data extend HuR’s role as a key regulator of TRAIL-induced apoptosis. Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients.