Abstract
BackgroundCelastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. However, the effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive.MethodsGlioma cells, including the U251, U87-MG and C6 cell lines and an animal model were used. The effects of celastrol on cells were evaluated by flow cytometry, confocal microscopy, reactive oxygen species production assay and immunoblotting after treatment of celastrol. Fisher’s exact test, a one-way ANOVA and the Mann-Whitney U-test were used to compare differences between groups. All data were analyzed using SPSS version 21.0 software.ResultsHere, we found that exposure to celastrol induced G2/M phase arrest and apoptosis. Celastrol increased the formation of autophagosomes, accumulation of LC3B and the expression of p62 protein. Celastrol-treated glioma cells exhibited decreased cell viability after the use of autophagy inhibitors. Additionally, autophagy and apoptosis caused by celastrol in glioma cells inhibited each other. Furthermore, celastrol induced JNK activation and ROS production and inhibited the activities of Akt and mTOR kinases. JNK and ROS inhibitors significantly attenuated celastrol-trigged apoptosis and autophagy, while Akt and mTOR inhibitors had opposite effects.ConclusionsIn conclusion, our study revealed that celastrol caused G2/M phase arrest and trigged apoptosis and autophagy by activating ROS/JNK signaling and blocking the Akt/mTOR signaling pathway.
Highlights
Celastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies
Celastrol inhibits the proliferation of glioma cells and exhibits low cytotoxicity towards astrocytes To investigate the antiproliferative activity and cytotoxicity of celastrol on glioma cells, U251, U87-MG and C6 cells were treated with various concentrations of celastrol for 12, 24, 36 and 48 h, and cell viability and morphology were measured by a Cell counting kit-8 (CCK8) assay and light microscopy, respectively
In conclusion, our study showed that the antitumor effects of celastrol in glioma cells are related to G2/M phase arrest and the triggering of autophagy and apoptosis via the activation of Reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling and blocking of the Akt/Mammalian target of rapamycin (mTOR) signaling pathway
Summary
A triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. The effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive. Temozolomide (TMZ) is the first-line chemotherapeutic drug for glioma treatment with a definite curative effect. Celastrol is a predominantly active natural product extracted from the root bark of TCM Tripterygium wilfordii and it has various biological properties, such as anti-tumor, immunosuppression and weight loss. Liu et al Journal of Experimental & Clinical Cancer Research (2019) 38:184 addition, celastrol has shown neuroprotective effects in various disease models (such as Parkinson’s Disease, Alzheimer’s Disease, and Amyotrophic Lateral Sclerosis), which means that celastrol can cross the blood–brain barrier [12, 13], which may be an advantage of celastrol in the treatment of intracranial tumors. The G2/M check point arrest is an effective mechanism adopted by many cytotoxic agents. The cyclinB1/cdc complex, which plays a key role in controlling the progression of the cell cycle by regulating the phosphorylation status of various proteins, is regulated by a series of proteins, including p21, Cdc25C, and Chk2 [15,16,17]
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