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

<div>Abstract<p>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.</p>Significance:<p>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.</p></div>