Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma.

Abstract

Rationale: Whole-genome sequencing has identified many amplified genes in esophageal squamous-cell carcinoma (ESCC). This study investigated the role and clinical relevance of these genes in ESCC. Methods: We collected ESCC and non-tumor esophageal tissues from 225 individuals who underwent surgery. Clinical data were collected and survival time was measured from the date of diagnosis to the date of last follow-up or death. Patient survival was compared with immunohistochemical staining score using Kaplan-Meier methods and hazard ratios were calculated by Cox models. Cells with gene overexpression and knockout were analyzed in proliferation, migration and invasion assays. Cells were also analyzed for levels of intracellular lactate, NADPH, ATP and mRNA and protein expression patterns. Protein levels in cell line and tissue samples were measured by immunoblotting or immunohistochemistry. ESCC cell were grown as xenograft tumors in nude mice. Primary ESCC in genetically engineered mice and patient-derived xenograft mouse models were established for test of therapeutic effects. Results: We show that TP53-induced glycolysis and apoptosis regulator (TIGAR) is a major player in ESCC progression and chemoresistance. TIGAR reprograms glucose metabolism from glycolysis to the glutamine pathway through AMP-activated kinase, and its overexpression is correlated with poor disease outcomes. Tigar knockout mice have reduced ESCC tumor burden and growth rates. Treatment of TIGAR-overexpressing ESCC cell xenografts and patient-derived tumor xenografts in mice with combination of glutaminase inhibitor and chemotherapeutic agents achieves significant more efficacy than chemotherapy alone. Conclusion: These findings shed light on an important role of TIGAR in ESCC and might provide evidence for targeted treatment of TIGAR-overexpressing ESCC.

• Authors: Jiahui Chu, Xiangjie Niu, Jiang Chang, Mingming Shao, Linna Peng, Yiyi Xi, Ai Lin, Chengcheng Wang, Qionghua Cui, Yingying Luo, Wenyi Fan, Yamei Chen, Yanxia Sun, Wenjia Guo, Wen Tan, Dongxin Lin, Chen Wu
• Journal: Theranostics (Theranostics) Vol. 10 Issue 8 Pg. 3488-3502 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32206103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Neoplasm Proteins
• Phosphoric Monoester Hydrolases
• TIGAR protein, human
• Glutaminase

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis Regulatory Proteins (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation
• Disease Progression
• Drug Delivery Systems
• Esophageal Neoplasms (drug therapy, genetics, mortality)
• Esophageal Squamous Cell Carcinoma (drug therapy, genetics, mortality)
• Female
• Glutaminase (antagonists & inhibitors)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (drug effects, genetics)
• Oncogenes
• Phosphoric Monoester Hydrolases (drug effects, genetics)
• Survival Rate
• Xenograft Model Antitumor Assays