MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1.
Ying YangMari B Ishak GabraEric A HanseXazmin H LowmanThai Q TranHaiqing LiNeta MilmanJuan LiuMichael A ReidJason W LocasaleZiv GilMei KongPublished in: Nature communications (2019)
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt to metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue. Mechanistically, miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumor growth in vivo. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumor microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.
Keyphrases
- induced apoptosis
- cell proliferation
- long non coding rna
- long noncoding rna
- cell cycle arrest
- poor prognosis
- signaling pathway
- endoplasmic reticulum stress
- endothelial cells
- cell death
- oxidative stress
- single cell
- dna damage
- stress induced
- stem cells
- blood pressure
- metabolic syndrome
- type diabetes
- mesenchymal stem cells
- pi k akt
- high intensity
- cell therapy
- wild type