Cancer-specific targeting of taurine upregulated gene 1 enhances the effects of chemotherapy in pancreatic cancer

概要

Background & Aims: Overcoming drug resistance is one of the biggest challenges in cancer chemotherapy. This study aimed to examine whether targeting a long non-coding RNA, taurine upregulated gene 1 (TUG1) could be an effective therapeutic approach to overcome drug resistance in pancreatic ductal adenocarcinoma (PDAC).

Methods: A total of 197 PDAC tissues were examined for TUG1 expression. The anti-tumor effect of TUG1 with cytotoxic agents, 5-Fluorouracil (5-FU) and Gemcitabine, was studied in multiple PDAC cell lines. Downstream miRNA and protein of TUG1 were examined by microarray-based analysis along with in silico analysis. Liquid chromatography-tandem mass spectrometry was used to measure the cellular concentration of 5-FU and its metabolites. The effect of antisense oligonucleotides against TUG1, coupled with cancer-specific drug delivery system (TUG1-DDS), was examined in PDAC xenograft models.

Results: PDACs showed significantly higher expression of TUG1 than the normal pancreatic tissues. Overall survival of PDAC patients 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 remarkably induced susceptibility to 5-FU in pancreatic cell lines, BxPC-3 and PK-9. Consistently, the cellular concentration of 5-FU was significantly higher under TUG1-depleted conditions. Intravenous treatment with TUG1-DDS and 5-FU significantly suppressed PDAC tumor growth in vivo compared to that by 5-FU treatment alone.

Conclusions: Our novel approach using TUG1-DDS in combination with 5-FU is 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.