Inhibition of pyruvate carboxylase reverses metformin resistance by activating AMPK in pancreatic cancer

被引：7

作者：

Liu, Chang ^{[1
]}

Zhou, Xiang ^{[2
]}

Ju, Huijun ^{[1
]}

Zhang, Yifan ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Nucl Med, Sch Med, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Renji Hosp, Dept Nucl Med, Sch Med, Shanghai, Peoples R China

来源：

LIFE SCIENCES | 2023年 / 327卷

基金：

中国国家自然科学基金;

关键词：

FDG uptake; PC; PDAC; OXPHOS; PGC-1 & alpha; Metformin; FATTY-ACID; CELLS; METABOLISM; GLYCOLYSIS; HALLMARKS; MITOCHONDRIA; PGC-1-ALPHA;

D O I：

10.1016/j.lfs.2023.121817

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Aims: Pyruvate carboxylase (PC) plays a key role in cancer cell metabolic reprogramming. Whether metabolic reprogramming and PC are related in PDAC is unclear. Here, the effect of PC expression on PDAC tumorigenesis and metabolic reprogramming were evaluated. Materials and methods: PC protein expression in PDAC and precancerous tissues was measured through immunohistochemistry. The maximum standardized uptake (SUVmax) of F-18-fluoro-2-deoxy-2-D-glucose (F-18-FDG) in PDAC patient PET/CT scans before surgical resection was retrospectively determined. Stable PC-knockdown and PC-overexpressing cells were established using lentiviruses, and PDAC progression was assessed in vivo and in vitro. Lactate content,F-18-FDG cell uptake rate, mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured in cells. RNA sequencing revealed and qPCR verified differentially expressed genes (DEGs) after PC knockdown. The signaling pathways involved were determined by Western blotting. Key findings: PC was significantly upregulated in PDAC tissues vs. precancerous tissues. A high SUVmax correlated with PC upregulation. PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1a) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT1A)regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression. Significance: PDAC cell uptake of FDG was positively correlated with PC expression. PC promotes PDAC glycolysis, and reducing PC expression can increase PGC1a expression, activate AMPK, and restore metformin sensitivity.

引用

页数：13

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