4.8 Article

Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer

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CANCER RESEARCH
卷 81, 期 7, 页码 1654-1666

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-3021

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  1. P-CREATE, Japan Agency for Medical Research and Development [19cm0106108h0004, 19cm0106202s0404, 17cm0106202h0002]
  2. Japan Society for the Promotion of Science [17H03582, 20H03511]
  3. JST/PRESTO [JPMJPR17H7]
  4. Research Grant of the Princess Takamatsu Cancer Research Fund [15-24712]
  5. Grants-in-Aid for Scientific Research [20H03511, 17H03582] Funding Source: KAKEN

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The study shows that targeting TUG1 can impact the sensitivity of pancreatic cancer cells to 5-FU, and treatment with TUG1-DDS can effectively suppress PDAC tumor growth. This novel approach may offer a new combinatorial strategy for cancer treatment.
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] .

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