Cao Bo, Deng Huan, Cui Hao, Zhao Ruiyang, Li Hanghang, Wei Bo, Chen Lin
Medical School of Chinese PLA, Beijing, 100853, China.
Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Cancer Cell Int. 2021 Sep 10;21(1):481. doi: 10.1186/s12935-021-02193-3.
Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC.
Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism.
Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo.
Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.
磷酸葡萄糖变位酶1（PGM1）在葡萄糖代谢中起重要调节作用。然而，PGM1在胃癌（GC）中的作用仍不清楚。本研究旨在探讨PGM1的作用，并基于GC的代谢重编程开发新的治疗方案。
基于癌症基因组图谱数据库对PGM1进行相关性和富集分析。分析来自Kaplan-Meier Plotter数据库的数据，以评估PGM1表达与GC患者生存时间之间的相关性。使用细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷、流式细胞术检测、皮下肿瘤生成和肺转移小鼠模型来确定体内外的生长和转移情况。通过一系列糖酵解指标检测细胞糖酵解，包括乳酸、丙酮酸、ATP生成和葡萄糖摄取。测定脂肪酸合酶（FASN）活性和脂质酶的表达水平以反映脂质代谢情况。
相关性和富集分析表明，PGM1与细胞活力、增殖和代谢密切相关。PGM1在GC组织和细胞系中过表达。高PGM1表达是特定亚群GC患者生存时间较短的指标。它还与GC的病理肿瘤分期和病理肿瘤淋巴结转移分期相关。在葡萄糖剥夺条件下，敲低PGM1可显著抑制细胞活力、增殖和糖酵解，而脂质代谢增强。奥利司他作为一种旨在抑制FASN活性的药物，可有效诱导GC细胞凋亡并抑制脂质代谢。然而，奥利司他反而增加了糖酵解水平。在葡萄糖剥夺条件下敲低PGM1后，由于体外和体内糖酵解与脂质代谢的联合作用，奥利司他对GC进展表现出更显著的抑制作用。
葡萄糖剥夺条件下PGM1表达的下调增强了奥利司他的抗癌作用。这种联合应用可能是GC治疗的一种新策略。
