Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
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DOI：
10.1158/0008-5472.can-20-3021
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发表时间：
2021-04-01
期刊：
影响因子：
11.2
通讯作者：
Kondo, Yutaka
中科院分区：
文献类型：
--
作者：
Tasaki, Yoshihiko;Suzuki, Miho;Kondo, Yutaka
克服耐药性是癌症化疗中最大的挑战之一。在这项研究中，我们研究了靶向长非编码RNA牛磺酸上调基因1（TUG 1）是否可以成为克服胰腺导管腺癌（PDAC）耐药性的有效治疗方法。与正常胰腺组织相比，TUG 1在197个PDAC组织中以显著更高的水平表达。接受以5-FU为基础的化疗的PDAC患者中，高TUG 1组的总生存期短于低TUG 1组。在机制上，TUG 1拮抗miR-376 b-3 p并上调二氢嘧啶脱氢酶（DPD）。在BxPC-3和PK-9胰腺细胞系中，TUG 1消耗诱导对5-FU的敏感性。一致地，在TUG 1耗尽条件下，5-FU的细胞浓度显著更高。在PDAC异种移植模型中，与单独的5-FU治疗相比，用癌症特异性药物递送系统（TUG 1-DDS）和5-FU的静脉内治疗显著抑制PDAC肿瘤生长。这种使用TUG 1-DDS与5-EU组合的新方法可以作为一种有效的治疗选择，以减弱DPD活性并满足靶向PDAC细胞中适当的5-FU剂量要求，这可以减少化疗的全身不良反应。靶向TUG 1与癌症特异性药物递送系统偶联有效调节TUG 1过表达PDAC细胞中的5-FU催化剂，从而有助于癌症治疗的新的组合策略。[图形]。
Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. In this study, we examine whether targeting the long noncoding RNA taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). TUG1 was expressed at significantly higher levels across 197 PDAC tissues compared with normal pancreatic tissues. Overall survival of patients with PDAC who had undergone 5-FU-based chemotherapy was shorter in high TUG1 group than in low TUG1 group. Mechanistically, TUG1 antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). TUG1 depletion induced susceptibility to 5-FU in BxPC-3 and PK-9 pancreatic cell lines. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (TUG1-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using TUG1-DDS in combination with 5-EU may serve as an effective therapeutic option to attenuate DPD activity and meet appropriate 5-FU dosage requirements in targeted PDAC cells, which can reduce the systemic adverse effects of chemotherapy.Significance: Targeting TUG1 coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in TUG1-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment.[GRAPHICS].