c-Myc protects hepatocellular carcinoma cell from ferroptosis induced by glutamine deprivation via upregulating GOT1 and Nrf2.

Autor: Zhao Y; Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China., Wang Y; Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China., Miao Z; Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China., Liu Y; Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China., Yang Q; Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin Province, China. yangq@jlu.edu.cn.
Jazyk: angličtina
Zdroj: Molecular biology reports [Mol Biol Rep] 2023 Aug; Vol. 50 (8), pp. 6627-6641. Date of Electronic Publication: 2023 Jun 26.
DOI: 10.1007/s11033-023-08495-1
Abstrakt: Background: Glutamine metabolism is critical for development of hepatocellular carcinoma (HCC), which makes it a novel promising treatment target. However, clinical evidence suggested glutamine withdrawal therapy does not achieved the desired tumor suppression. Therefore, it is valuable to investigate the survival mechanisms of tumors with glutamine deprivation.
Methods: The HCC cells were cultured in glutamine-free medium or supplemented with glutamine metabolites or ferroptosis inhibitors. The parameters related to ferroptosis and the activity of GSH synthesis-related enzymes of the HCC cells were detected by corresponding kits. The expressions of glutamate oxaloacetate transaminase 1 (GOT1), c-Myc and Nrf2 were detected by western blot and qRT-PCR. The chromatin immunoprecipitation and luciferase reporter assays were performed to investigate the correlation between c-Myc and GOT1. The siRNAs of c-Myc and GOT1 were used to explore their roles in GSH (GSH) synthesis and ferroptosis in vitro and in vivo.
Results: Glutamine deprivation-induced ferroptosis did not completely inhibit HCC cells proliferation. Glutamine deprivation activated the expression of c-Myc, which promoted the transcription of GOT1 and Nrf2, consequently maintaining the GSH synthesis and inhibiting ferroptosis. In addition, combined inhibition of GOT1 with glutamine deprivation could result in better inhibition of HCC in vitro and in vivo.
Conclusions: In our work, the results indicate that GOT1 induced by c-Myc may play an important role in combating ferroptosis due to glutamine deprivation, making it a significant target in glutamine withdrawal therapy. This study provides a theoretical foundation for the clinical targeted therapy for HCC.
(© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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