A novel anti-cancer mechanism of Nutlin-3 through downregulation of Eag1 channel and PI3K/AKT pathway.

Abstract

Nutlin-3 shows a potent antitumor efficacy through downregulation of the cancerogenic ether à go-go 1 (Eag1) channel. However, the molecular mechanisms responsible for the regulation of Eag1 by Nutlin-3 in cancer cells remain unclear. In this study, we propose a novel anticancer mechanism of Nutlin-3, in which Nutlin-3 acts through the p53-Eag1-PI3K/AKT pathway. We first confirmed that Eag1 was downregulated through the activation of p53 by Nutlin-3. We then revealed that the inhibition of Eag1 electrophysiological function resulted in the decrease of viability, migration and invasion of HeLa cells. It is worth noting that the antitumor effect of Nutlin-3 was abolished in the Eag1 knockdown HeLa cell lines by siRNA. And Nutlin-3 can decrease the cell viability of H8 cells which were stably transfected with Eag1, but has no obvious inhibitory effect on blank H8 cells. Finally, we demonstrated that the decrease in Eag1 channel activity induced by Nutlin-3 treatment exerts anticancer activity by inhibiting the PI3K/AKT pathway. Our study therefore fills the gap between p53 pathway and its cellular function mediated by Eag1, shedding light on the new anti-cancer mechanism of Nutlin-3.

• Authors: Xuzhao Wang, Yafei Chen, Hui Liu, Shuai Guo, Yufeng Hu, Yong Zhan, Hailong An
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 517 Issue 3 Pg. 445-451 (09 24 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 31378368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Ether-A-Go-Go Potassium Channels
• Imidazoles
• KCNH1 protein, human
• Piperazines
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• nutlin 3
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Epithelial Cells (cytology, drug effects, metabolism)
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• HeLa Cells
• Humans
• Imidazoles (pharmacology)
• Organ Specificity
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)