Abstract
ObjectiveCelastrol has anti-cancer effects by increase of apoptosis of gastric cancer cells. However, its role in gastric cancer cell cycle is still unclear. The aim of this study was to investigate the effect and mechanism of celastrol on gastric cancer cell cycle.MethodsThe effects of celastrol on cell cycle in BGC-823 and MGC-803 cells were assayed via flow cytometry analysis. The expression of p27 and mTOR was detected by real-time PCR and western blot. The activity of mTOR and mTORC2 was measured by mTOR and mTORC2 kinase assays. miR-21 mimic was used to up-regulate miR-21 expression and mTOR expression plasmid was used to increase mTOR level in gastric cancer cells.ResultsCelastrol caused G2/M cell-cycle arrest that was accompanied by the down-regulation of miR-21 expression. In particular, miR-21 overexpression reversed cell cycle arrest effects of celastrol. Further study showed that celastrol increased levels of the p27 protein by inhibiting its degradation. miR-21 and mTOR signaling pathway was involved in the increase of p27 protein expression in BGC-823 and MGC-803 cells treated with celastrol. Significantly, miR-21 overexpression restored the decrease of mTOR activity in cells exposed celastrol.ConclusionsThe effect of celastrol on cell cycle arrest of gastric cancer cells was due to an increase of p27 protein level via inhibiting miR-21-mTOR signaling pathway.
Highlights
There is increasing evidence demonstrating uncontrolled gastric cancer cell growth is due to disruption of the G1/S and G2/M checkpoints, which is involved in a series of positive and negative cell-cycle regulators [1, 2]
Consistent to our previous study [18], we found that miR-21 expression was decreased in BGC-823 and MGC803 cells treated with celastrol
Up‐regulation of miR‐21 can reverse the effect of celastrol on cell cycle arrest This assay was conducted to investigate whether miR21 was involved in the effect of celastrol on cell cycle arrest in gastric cancer cells
Summary
There is increasing evidence demonstrating uncontrolled gastric cancer cell growth is due to disruption of the G1/S and G2/M checkpoints, which is involved in a series of positive and negative cell-cycle regulators [1, 2]. Accumulating evidence suggests p27 was a useful predictive marker of prognosis of gastric cancer. The decrease of p27 expression facilitates tumor growth and correlates with clinical invasiveness of the tumors, while high expression of p27 was associated with a favorable prognosis [4, 5]. MicroRNA-21 (miR-21) plays an important role in regulating gastric cancer cell proliferation and migration [6]. High miR-21 expression predicts poorer survival in patients with gastric cancer [7]. When the expression of miR-21 was down-regulated in human gastric cancer, it was showed to inhibit cell proliferation [9]
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