Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis

摘要

Background: Acidic microenvironment is a common physiological phenomenon in tumors, and is closely related to cancer development, but the effects of acidosis on pancreatic adenocarcinoma (PDAC) remains to be elucidated. @@@ Methods: Metabonomic assay and transcriptomic microarray were used to detect the changes of metabolites and gene expression profile respectively in acidosis-adapted PDAC cells. Wound healing, transwell and in vivo assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation assays were performed to determine cell proliferation. @@@ Results: The acidosis-adapted PDAC cells had stronger metastasis and proliferation ability compared with the control cells. Metabonomic analysis showed that acidosis-adapted PDAC cells had both increased glucose and decreased glycolysis, implying a shift to pentose phosphate pathway. The metabolic shift further led to the inactivation of AMPK by elevating ATP. Transcriptomic analysis revealed that the differentially expressed genes in acidosis-adapted cells were enriched in extracellular matrix modification and Hippo signaling. Besides, MMP1 was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway, but could be reduced by AMPK activator. @@@ Conclusion: The present study showed that metabolic reprogramming promotes proliferation and metastasis of acidosis-adapted PDAC cells by inhibiting AMPK/Hippo signaling, thus upregulating MMP1.

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