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

• Published in: International journal of biological sciences 2022-01, Vol.18 (6), p.2304-2316
• Main Authors: Chen, Siyuan, Ning, Bo, Song, Jinwen, Yang, Zihan, Zhou, Li, Chen, Zhiji, Mao, Linhong, Liu, Hongtao, Wang, Qingliang, He, Song, Zhou, Zhihang
• Format: Article
• Language: English
• Subjects: Acidosis; Acidosis - genetics; Adenocarcinoma; Adenocarcinoma - genetics; AMP-Activated Protein Kinases - metabolism; Assaying; Carcinoma, Pancreatic Ductal - metabolism; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Colorectal cancer; Dehydrogenases; DNA microarrays; Extracellular matrix; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Glucose; Glycolysis; Humans; Inactivation; Kinases; Matrix Metalloproteinase 1 - genetics; Medical prognosis; Metabolism; Metabolites; Metastases; Metastasis; Microenvironments; Pancreas; Pancreatic Neoplasms; Pancreatic Neoplasms - metabolism; Pentose; Pentose phosphate pathway; Pentose Phosphate Pathway - genetics; Research Paper; Signal transduction; Signaling; Software; Transcriptomics; Tumor Microenvironment - genetics; Tumors; Values; Wound healing; Yes-associated protein
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.69526

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. : 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 assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation assays were performed to determine cell proliferation. 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. : The present study showed that metabolic reprogramming promotes proliferation and metastasis of acidosis-adapted PDAC cells by inhibiting AMPK/Hippo signaling, thus upregulating MMP1.