GSE125538
MiR-135 suppresses glycolysis and promotes adaptation to metabolic stress in pancreatic cancer cells by targeting phosphofructokinase-1
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 and survive in metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue and represses aerobic glycolysis. Mechanistically, we found that 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 deficient PDAC cells preferentially use glutamine carbon to replenish the TCA cycle, and miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumour growth in vivo. Consistent with these findings, patient pancreatic cancer tissue displays decreased PFK1 level compared to adjacent normal tissue. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumour microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses. Overall design: Detect the difference of miRNA expression between pancreatic cancer tumor tissue and adjacent normal tissue