| Autor: |
Chiu CF; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110, Taiwan.; Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan., Lin HR; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110, Taiwan., Su YH; Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan., Chen HA; Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan., Hung SW; Division of Animal Industry, Animal Technology Laboratories, Agricultural Technology Research Institute, Xiangshan Dist., Hsinchu City 300, Taiwan., Huang SY; Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110, Taiwan.; School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110, Taiwan. |
| Abstrakt: |
Dicer, a cytoplasmic type III RNase, is essential for the maturation of microRNAs (miRNAs) and is implicated in cancer progression and chemoresistance. Our previous research demonstrated that phosphorylation of Dicer at S1016 alters miRNA maturation and glutamine metabolism, contributing to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on the role of Dicer phosphorylation at S1728/S1852 in GEM-resistant PDAC cells. Using shRNA to knock down Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells, we examined cell viability through MTT and clonogenic assays. We also expressed phosphomimetic Dicer 2E (S1728E/S1852E) and phosphomutant Dicer 2A (S1728A/S1852A) to evaluate their effects on GEM resistance and metabolism. Our results show that phosphorylation at S1728/S1852 promotes GEM resistance by reprogramming glutamine metabolism. Specifically, phosphomimetic Dicer 2E increased intracellular glutamine, driving pyrimidine synthesis and raising dCTP levels, which compete with gemcitabine's metabolites. This metabolic shift enhanced drug resistance. In contrast, phosphomutant Dicer 2A reduced GEM resistance. These findings highlight the importance of Dicer phosphorylation in regulating metabolism and drug sensitivity, offering insights into potential therapeutic strategies for overcoming GEM resistance in pancreatic cancer. |
