Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer
- 1 March 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (7), 1654-1666
- https://doi.org/10.1158/0008-5472.can-20-3021
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 (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-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 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. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpgFunding Information
- Japan Agency for Medical Research and Development (19cm0106108h0004)
- Japan Agency for Medical Research and Development (19cm0106202s0404)
- Japan Agency for Medical Research and Development (17cm0106202h0002)
- Japan Society for the Promotion of Science (17H03582, 20H03511)
- JST/PRESTO grant (JPMJPR17H7)
This publication has 49 references indexed in Scilit:
- Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapyFrontiers in Pharmacology, 2013
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Phenotype and Genotype of Pancreatic Cancer Cell LinesPancreas, 2010
- Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasisNature, 2010
- Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine‐based chemotherapy: Evidence from 24 studiesInternational Journal of Cancer, 2008
- The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolitesMolecular Cancer Therapeutics, 2005
- Evaluation of Combination ChemotherapyClinical Cancer Research, 2004
- Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracilEuropean Journal of Cancer, 2004
- Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulatorsAnti-Cancer Drugs, 1996
- Establishment of six human pancreatic cancer cell lines and their sensitivities to anti-tumor drugs.The Tohoku Journal of Experimental Medicine, 1986