Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m(6)A-Based Epitranscriptomic Mechanism
| Autor: | Xiaochuan Liu, Xiaoxia Dai, Jun Yuan, Weili Miao, Yinsheng Wang, David Bade, Lin Li, Yuxiang Sun, Ming Huang, Gwendolyn Gonzalez |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Untranslated region
Adenosine Translational efficiency Antineoplastic Agents Hormonal p38 mitogen-activated protein kinases Adenylate kinase Apoptosis Breast Neoplasms Transfection Methylation 03 medical and health sciences 0302 clinical medicine Drug Discovery Genetics medicine Humans RNA Messenger skin and connective tissue diseases Molecular Biology 030304 developmental biology Cell Proliferation Pharmacology 0303 health sciences Chemistry Adenylate Kinase Methyltransferases Cell biology Gene Expression Regulation Neoplastic Tamoxifen HEK293 Cells Drug Resistance Neoplasm 030220 oncology & carcinogenesis MCF-7 Cells Molecular Medicine Phosphorylation Original Article Female Reactive Oxygen Species medicine.drug Signal Transduction |
| Zdroj: | Mol Ther |
| Popis: | N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mRNA and this methylation constitutes an important regulatory mechanism for the stability and translational efficiency of mRNA. In this study, we found that the protein levels of adenylate kinase 4 (AK4) and m(6)A writer METTL3 are significantly higher in tamoxifen-resistant (TamR) MCF-7 cells than in parental cells. The TamR MCF-7 cells also exhibit increased methylation at multiple m(6)A consensus motif sites in the 5′ untranslated region (5′ UTR) of AK4 mRNA, and genetic depletion of METTL3 in TamR MCF-7 cells led to a diminished AK4 protein level and attenuated resistance to tamoxifen. In addition, we observed augmented levels of reactive oxygen species (ROS) and p38 activity in TamR MCF-7 cells, and both are diminished upon genetic depletion of AK4. Reciprocally, overexpression of AK4 in MCF-7 cells stimulates ROS and p38 phosphorylation levels, and it suppresses mitochondrial apoptosis. Moreover, scavenging of intracellular ROS leads to reduced p38 activity and re-sensitizes TamR MCF-7 cells to tamoxifen. Thus, our results uncover a novel m(6)A-mediated epitranscriptomic mechanism for the regulation of AK4, illustrate the cellular pathways through which increased AK4 expression contributes to tamoxifen resistance, and reveal AK4 as a potential therapeutic target for overcoming tamoxifen resistance. |
| Databáze: | OpenAIRE |
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