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

Abstract

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 (<i>TUG1</i>) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC). <i>TUG1</i> 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 <i>TUG1</i> group than in low <i>TUG1</i> group. Mechanistically, <i>TUG1</i> antagonized miR-376b-3p and upregulated dihydropyrimidine dehydrogenase (DPD). <i>TUG1</i> 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 <i>TUG1</i>-depleted conditions. In PDAC xenograft models, intravenous treatment with a cancer-specific drug delivery system (<i>TUG1</i>-DDS) and 5-FU significantly suppressed PDAC tumor growth compared with 5-FU treatment alone. This novel approach using <i>TUG1</i>-DDS in combination with 5-FU 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 <i>TUG1</i> coupled with a cancer-specific drug delivery system effectively modulates 5-FU catabolism in <i>TUG1</i>-overexpressing PDAC cells, thus contributing to a new combinatorial strategy for cancer treatment. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/7/1654/F1.large.jpg.