[en] Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease. SIGNIFICANCE: This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Hu, Qiangsheng; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Qin, Yi; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China ; Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China
Ji, Shunrong; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Shi, Xiuhui ✱; Université de Liège - ULiège > Département de pharmacie ; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Dai, Weixing; Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, China
Fan, Guixiong; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Li, Shuo; Shanghai Pancreatic Cancer Institute, Shanghai, China
Xu, Wenyan; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Liu, Wensheng; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Liu, Mengqi; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Zhang, Zheng; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Ye, Zeng; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Zhou, Zhijun ; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Yang, Jingxuan ; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Zhuo, Qifeng; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Yu, Xianjun; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
Li, Min; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. xuxiaowu@fudanpci.org Min-Li@ouhsc.edu
Xu, Xiaowu; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. xuxiaowu@fudanpci.org Min-Li@ouhsc.edu ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China ; Shanghai Pancreatic Cancer Institute, Shanghai, China ; Pancreatic Cancer Institute, Fudan University, Shanghai, China
NSCF - National Natural Science Foundation of China
Funding text :
The authors thank Huanyu Xia for providing assistance with the clinical data collection. This research was supported by the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057) and National Science Foundation for Distinguished Young Scholars of China (81625016 to X. Yu); National Natural Science Foundation of China (81871950 to Y. Qin); and National Natural Science Foundation of China (81972250 to X. Xu).
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