Characteristic ASS1 and PYCR1 Maintain Esophageal Squamous Cell Carcinoma Development Under Limited Nutrient Conditions

Abstract

Cancer cells develop under nutrient and oxygen deficient microenvironment caused by insufficient vascularization. Reprogramming metabolism meets the needs of the rapid growth of cancer cells in nutrient stress conditions. But the precise mechanism of metabolic abnormalities in esophageal squamous cell carcinoma (ESCC) remains largely unclear. Using omics technology, we measured the changes of metabolic enzymes and pathways on ESCC under the microenvironment of hypoxia and nutrient deficiency. Consequently, the expression of argininosuccinate synthetase 1 (ASS1) and pyrroline-5-carboxylate reductase 1 (PYCR1) was enhanced and may promoted the proliferation and migration of ESCC by its catalyzed metabolites. Clinically, high levels of ASS1 and PYCR1 were significantly associated with advanced stages and metastasis, even early stage compared to intraepithelial neoplasia. In mechanism, IGF1R regulated ASS1 and PYCR1 by affecting IGF1R - Ras/MAPK - c-MYC axis. In vivo, ASS1 and PYCR1 could promote tumor growth and chemotherapeutic resistance. In summary, enhanced ASS1 and PYCR1 induces ESCC tolerance to nutrient stress and maintains cancer development and IGF1R-cMYC axis is the key factor upregulating ASS1 and PYCR under harsh conditions. The study also provides a molecular aspect for developing biomarkers of ESCC and therapeutic benefits of targeting IGF1R/ASS1/PYCR1 axis. Funding Information: This study was supported by grants from The Top- level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-04), National Natural Science Foundation of China (82073224, 82072684 and 81872351) and Shanghai Committee of Science and Technology (18140900100) Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: This study was approved by the institutional review board of Shanghai East Hospital, School of Medicine, Tongji University. The in vivo study was approved by the animal care and use committee of Tongji University.