Abstract
2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective COX-2 inhibitor celecoxib that lacks COX-2-inhibitory function. Thus, DMC is a promising drug for anti-tumor. In this study, we evaluated the efficacy and the molecular basis of DMC in the treatment of human glioblastoma multiforme (GBM). DMC inhibited the growth and proliferation of GBM cell lines (LN229, A172, U251, and U87MG) in a dose-dependent manner (P < 0.001). In GBM cells treated with DMC, detection by flow cytometry showed cell cycle arrest, and proteins involved in cell cycle such as P21 were increased. Compared with control group, Annexin-V/PI-staining in DMC-treatment group was increased, indicating that DMC could induce apoptosis in GBM cells. Also, associated proteins including cleaved caspase 3 and cleaved PARP-1 were increased. It was further explored whether DMC blocked cell cycle and induced apoptosis in GBM cells through CIP2A/PP2A/AKT signaling pathway. After treatment of DMC, the phosphorylation of Akt was reduced while the total Akt level was not affected. DMC suppressed the expression of CIP2A in a time-dependent manner, while the CIP2A overexpression group reversed cell cycle and apoptotic protein expression led by DMC. Finally, in a xenograft model in nude mice using LN229 cells, DMC suppressed tumor growth. These findings proved that DMC could block cell cycle and induce apoptosis in GBM cells by suppressing CIP2A/PP2A/Akt signaling axis, which indicated that DMC could be an effective option for GBM treatment.
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Data Availability
The data sets generated and analyzed in the current study are available from the corresponding author on reasonable request.
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Acknowledgements
Thanks are due to Anjing Chen, Guo Xiang, Qing Zhang, and Wenjie Li for technical assistance.
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This work was supported by the Key Technology Research and Development Program of Shandong [Grant number 2017GSF218028, Feng Li]
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Dezheng Gao: conception and design, perform experiments, write the article, critical revision of the article; Alphonce M.K Nyalali, Yongqiang Hou, Yongxiang Xu, Junli Zhou, Wenguo Zhao, and Bin Huang: perform experiments, data analysis; Feng Li: conception and design, write the article, critical revision of the article.
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The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) of Shandong University and performed under the guidance of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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Gao, D., Nyalali, A.M.K., Hou, Y. et al. 2,5-Dimethyl Celecoxib Inhibits Proliferation and Cell Cycle and Induces Apoptosis in Glioblastoma by Suppressing CIP2A/PP2A/Akt Signaling Axis. J Mol Neurosci 71, 1703–1713 (2021). https://doi.org/10.1007/s12031-020-01773-8
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DOI: https://doi.org/10.1007/s12031-020-01773-8