Carnosine suppresses human glioma cells under normoxic and hypoxic conditions partly via inhibiting glutamine metabolism

Yu-jia Fang1, Ming Wu1, Hai-ni Chen1, Tian-tian Wen1, Jian-xin Lyu1,2, Yao Shen1
1 Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou 325035, China
2 Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
Correspondence to: Yao Shen:,
DOI: 10.1038/s41401-020-0488-1
Received: 24 March 2020
Accepted: 19 July 2020
Advance online: 11 August 2020


L-Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide, which has shown broad-spectrum anticancer activity. But the anticancer mechanisms and regulators remain unknown. In this study, we investigated the effects of carnosine on human glioma U87 and U251 cell lines under normoxia (21% O2) and hypoxia (1% O2). We showed that carnosine (25−75 mM) dose-dependently inhibited the proliferation of the glioma cells; carnosine (50 mM) inhibited their colony formation, migration, and invasion capacity. But there was no significant difference in the inhibitory effects of carnosine under normoxia and hypoxia. Treatment with carnosine (50 mM) significantly decreased the expression of glutamine synthetase (GS) at the translation level rather than the transcription level in U87 and U251 cells, both under normoxia and hypoxia. Furthermore, the silencing of GS gene with shRNA and glutamine (Gln) deprivation significantly suppressed the growth, migratory, and invasive potential of the glioma cells. The inhibitory effect of carnosine on U87 and U251 cells was partly achieved by inhibiting the Gln metabolism pathway. Carnosine reduced the expression of GS in U87 and U251 cells by promoting the degradation of GS through the proteasome pathway, shortening the protein half-life, and reducing its stability. Given that targeting tumor metabolism is a proven efficient therapeutic tactic, our results may present new treatment strategies and drugs for improving the prognosis of gliomas.
Keywords: glioma; hypoxia; carnosine; glutamine synthetase; proteasome; tumor metabolism

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