Tryptophan deficiency induced by indoleamine 2,3‐dioxygenase 1 results in glucose transporter 1‐dependent promotion of aerobic glycolysis in pancreatic cancer
Heng Liang,
Jiani Zhan,
Yunqiu Chen,
Zikang Xing,
Zhen Ning Tony He,
Yuying Liu,
Xuewen Li,
Yijia Chen,
Zhiyao Li,
Chunxiang Kuang,
Dan Yang,
Qing Yang
Affiliations
Heng Liang
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Jiani Zhan
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Yunqiu Chen
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Zikang Xing
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Zhen Ning Tony He
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Yuying Liu
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Xuewen Li
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Yijia Chen
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Zhiyao Li
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Chunxiang Kuang
Shanghai Key Lab of Chemical Assessment and Sustainability School of Chemical Science and Engineering Tongji University Shanghai China
Dan Yang
Department of Orthopedics Shanghai Children's Hospital School of Medicine Shanghai Jiao Tong University Shanghai China
Qing Yang
State Key Laboratory of Genetic Engineering School of Life Sciences MOE Engineering Research Center of Gene Technology Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai China
Abstract Indoleamine 2,3‐dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1–glycolysis–apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.
