Artesunate inhibits the mevalonate pathway and promotes glioma cell senescence

Autor: Shupei Wei, Zhiyu Chen, Yingjie Nie, Wenli Yin, Yingzi Liu, Qianying Ouyang, Tao Chen, Lili Liu, Feiyue Zeng
Rok vydání: 2019
Předmět:
0301 basic medicine
Senescence
Cyclin-Dependent Kinase Inhibitor p21
senescence
Transcription
Genetic
Cell
Artesunate
Mevalonic Acid
Models
Biological
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
distant seeding
Cell Movement
Glioma
Cell Line
Tumor
glioma
medicine
Humans
Cellular Senescence
Cell Proliferation
Cell Nucleus
Brain Neoplasms
mevalonate pathway
Cell Biology
Original Articles
medicine.disease
Protein Transport
030104 developmental biology
medicine.anatomical_structure
chemistry
Drug development
Cell culture
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Hydroxymethylglutaryl CoA Reductases
Original Article
Mevalonate pathway
Tumor Suppressor Protein p53
Nuclear localization sequence
Metabolic Networks and Pathways
Protein Binding
Sterol Regulatory Element Binding Protein 2
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
Popis: Glioma is a common brain malignancy for which new drug development is urgently needed because of radiotherapy and drug resistance. Recent studies have demonstrated that artemisinin (ARS) compounds can display antiglioma activity, but the mechanisms are poorly understood. Using cell lines and mouse models, we investigated the effects of the most soluble ARS analogue artesunate (ART) on glioma cell growth, migration, distant seeding and senescence and elucidated the underlying mechanisms. Artemisinin effectively inhibited glioma cell growth, migration and distant seeding. Further investigation of the mechanisms showed that ART can influence glioma cell metabolism by affecting the nuclear localization of SREBP2 (sterol regulatory element‐binding protein 2) and the expression of its target gene HMGCR (3‐hydroxy‐3‐methylglutaryl coenzyme A reductase), the rate‐limiting enzyme of the mevalonate (MVA) pathway. Moreover, ART affected the interaction between SREBP2 and P53 and restored the expression of P21 in cells expressing wild‐type P53, thus playing a key role in cell senescence induction. In conclusion, our study demonstrated the new therapeutic potential of ART in glioma cells and showed the novel anticancer mechanisms of ARS compounds of regulating MVA metabolism and cell senescence.
Databáze: OpenAIRE
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