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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Increase in Cisplatin Resistance by MeCP2 in Human Gastric Cancer through the Activation of the AKT Pathway by Facilitating PDK-1 Transcription

Author(s): Bo Guo, Shuang Cai, Wen Li, Chen Guo, Yijie Liu, Xiaoping Ma, Hailin Ma and Lingyu Zhao*

Volume 22, Issue 5, 2022

Published on: 22 April, 2022

Page: [414 - 425] Pages: 12

DOI: 10.2174/1568009622666220223115216

Price: $65

Abstract

Background: Increasing evidence indicates that an imbalance in oncogenes is implicated in cancer chemotherapy resistance. Methyl-CpG binding protein 2 (MeCP2), which acts as a major epigenetic regulator of the expression of various genes, is involved in the carcinogenesis and progression of gastric cancer. However, is it not known whether the role of MeCP2 is vital in acquired cisplatin resistance in gastric cancer.

Objective: This study aimed to determine whether inhibition of MeCP2 expression could sensitize DDP-resistant GC cells to DDP and elucidate the underlying molecular mechanism.

Methods: qRT-PCR and western blotting were used to evaluate MeCP2 expression in DDP-resistant GC cells. Subsequently, cell viability, colony formation, cell cycle, apoptosis, and tumorigenicity assays were performed to explore the in vitro and in vivo roles of MeCP2. Chromatin immunoprecipitation- qPCR and luciferase reporter assays were used to identify whether 3-phosphoinositide-dependent protein kinase 1 (PDK-1) was a direct target gene of MeCP2.

Results: MeCP2 was upregulated in malignant DDP-resistant cells compared to non-DDP-resistant GC cells or normal gastric epithelial cells. MeCP2 knockdown increased the sensitivity of DDP-resistant GC cells to DDP, resulting in reduced cell growth, G0/G1 phase arrest, and increased apoptosis, whereas MeCP2 overexpression attenuated DDP sensitivity of DDP-resistant GC cells. In addition, MeCP2 knockdown enhanced DDP sensitivity in vivo. MeCP2 elevated PDK-1 expression by binding to CpG sites in promoter regions, and inhibition of PDK-1 reversed the inductive effect of MeCP2 overexpression on DDP resistance in GC cells.

Conclusion: These findings indicate that silencing of MeCP2 may potentiate DDP-induced cell death, thereby providing a promising therapeutic strategy for GC.

Keywords: Chemotherapy resistance, cisplatin, MeCP2, PDK-1, gastric cancer, DDP sensitivity.

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