Int J Biol Sci 2022; 18(6):2304-2316. doi:10.7150/ijbs.69526 This issue

Research Paper

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

Siyuan Chen1*, Bo Ning1*, Jinwen Song2, Zihan Yang3, Li Zhou1, Zhiji Chen1, Linhong Mao1, Hongtao Liu1, Qingliang Wang4, Song He1, Zhihang Zhou1✉

1. Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, China.
2. Department of Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
3. Department of Biomedical Science, City University of Hong Kong, Hong Kong SAR, China.
4. Department of Pathology, the Second Affiliated Hospital of Chongqing Medical University, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chen S, Ning B, Song J, Yang Z, Zhou L, Chen Z, Mao L, Liu H, Wang Q, He S, Zhou Z. Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis. Int J Biol Sci 2022; 18(6):2304-2316. doi:10.7150/ijbs.69526. Available from https://www.ijbs.com/v18p2304.htm

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Abstract

Graphic abstract

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.

Keywords: Acidic microenvironment, PDAC, Metastasis, MMP1, Hippo signaling, AMPK