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

作者全名："Chen, Siyuan; Ning, Bo; Song, Jinwen; Yang, Zihan; Zhou, Li; Chen, Zhiji; Mao, Linhong; Liu, Hongtao; Wang, Qingliang; He, Song; Zhou, Zhihang"

作者地址："[Chen, Siyuan; Ning, Bo; Zhou, Li; Chen, Zhiji; Mao, Linhong; Liu, Hongtao; He, Song; Zhou, Zhihang] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China; [Song, Jinwen] Chinese Peoples Liberat Army Gen Hosp, Natl Clin Res Ctr Infect Dis, Med Ctr 5, Dept Infect Dis, Beijing, Peoples R China; [Yang, Zihan] City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China; [Wang, Qingliang] Chongqing Med Univ, Dept Pathol, Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Zhou, ZH (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China."

来源：INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000831182700006

JCR分区：Q1

影响因子：9.2

年份：2022

卷号：18

期号：6

开始页：2304

结束页：2316

文献类型：Article

关键词：Acidic microenvironment PDAC; Metastasis; MMP1; Hippo signaling; AMPK

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."

基金机构："National Natural Science Fund [81972285]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [13-002-011, 13-004-009]"

基金资助正文："We sincerely appreciate all lab members. This study was funded by the National Natural Science Fund (No. 81972285), Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (13-002-011, 13-004-009)."