Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells

Abstract

Background Celastrol, 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. Methods Glioma 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. Results Here, 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. Conclusions In 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1173-4) contains supplementary material, which is available to authorized users.

<p>Polyphyllin VI Induces Apoptosis and Autophagy via Reactive Oxygen Species Mediated JNK and P38 Activation in Glioma</p>

“…In glioma, Celastrol has been reported to inhibit human glioma by mediating autophagy and apoptosis. 15 In the current study, we describe the ability of PPVI, the main active ingredient extracted from Paris polyphylla, to exhibit cytotoxicity in various malignancies. 6,20,23,24 We reveal the anti-tumor effects of this compound, in the suppression of cell proliferation and migration, blocking cell cycle progression as well as the induction of autophagy and apoptosis.…”

“…13 Accumulating evidence shows that chemotherapeutics can simultaneously modulate both apoptosis and autophagy. 14,15 However, the relationship between the two types of programmed cell death remains unclear. Reactive oxygen species (ROS) are produced in mitochondria, where are also the main targets of ROS.…”

Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

“…We found that pretreatment with NAC markedly reversed JNK phosphorylation induced by the combined treatment in CAL27 and CAL27/CDDP cells (Figures 8(d) and 8(j)). Furthermore, many evidences suggest that ROS plays an important role in mediating the AKT/mTOR signaling pathway [31,32]. Therefore, we explored whether the combination treatment can downregulate the AKT/mTOR signaling pathway via regulating the ROS in TSCC cells.…”

“…Studies have suggested that activation of ROS/JNK and inhibition of the AKT/mTOR signaling pathway can effectively induce apoptosis and autophagy in cancer cells [31]. Therefore, we have further explored the underlying mechanism of combination treatment to induce apoptosis and autophagy.…”

Celastrol ameliorates endoplasmic stress-mediated apoptosis of osteoarthritis via regulating ATF-6/CHOP signalling pathway

“…[ 13 ] It also indicated that celastrol has potential anti‐apoptotic effect by affecting Akt and p38 MAPK signalling pathways. [ 14 ] Moreover, celastrol can attenuate pain and cartilage damage in OA rats. [ 15 ] Therefore, we hypothesized that celastrol may be effective in improving OA by reducing chondrocyte apoptosis rate via regulating ER stress pathway.…”