5-Demethylnobiletin mediates cell cycle arrest and apoptosis via the ERK1/2/AKT/STAT3 signaling pathways in glioblastoma cells

Xuehua Zhang; Leilei Zhao; Jinlong Xiao; Yudi Wang; Yunmeng Li; Chaoqun Zhu; He Zhang; Yurui Zhang; Xiao Zhu; Yucui Dong

doi:10.3389/fonc.2023.1143664

5-Demethylnobiletin mediates cell cycle arrest and apoptosis via the ERK1/2/AKT/STAT3 signaling pathways in glioblastoma cells

Front Oncol. 2023 Apr 17:13:1143664. doi: 10.3389/fonc.2023.1143664. eCollection 2023.

Authors

Xuehua Zhang¹, Leilei Zhao¹, Jinlong Xiao¹, Yudi Wang¹, Yunmeng Li¹, Chaoqun Zhu², He Zhang³, Yurui Zhang¹, Xiao Zhu², Yucui Dong¹

Affiliations

¹ Department of Immunology, Binzhou Medical University, Yantai, China.
² School of Computer and Control Engineering, Yantai University, Yantai, China.
³ Department of Immunology, Qiqihar Medical University, Qiqihar, China.

Abstract

5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug.

Keywords: 5-Demethylnobiletin; AKT; ERK1/2; STAT3; cell apoptosis; cell cycle arrest; glioblastoma.

Grants and funding

This work was supported by the Shandong Provincial Natural Science Foundation of China (ZR2021MH036 to Y-C D); the National Natural Science Foundation of China (61902094 to XZ (Xiao Zhu)); the Science and Technology Program of Binzhou Medical University (50012304325 to Y-C D).