Small molecule NMD and MDM2 inhibitors synergistically trigger apoptosis in HeLa cells
1Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, PR China; Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, PR China.
Abstract:
The nonsense-mediated mRNA decay (NMD) pathway and the p53 pathway, linked to tumorgenesis, are also promising targets for cancer treatment. NMD plays an important role in RNA quality control, while the p53 pathway is involved in cancer suppression. However, their individual and combined effects on cervical cancer are poorly understood. In this study, we evaluated the impacts of NMD inhibitor, Mouse double minute 2 homolog (MDM2) inhibitor, and their combination on cell apoptosis, cell cycle, and p53 target genes in human papillomavirus-18-positive HeLa cells. Our findings revealed that XR-2 failed to activate p53 or induce apoptosis in HeLa cells, whereas SMG1 (serine/threonine-protein kinase 1) inhibitor repressed cell proliferation at high concentrations. Notably, the combination of these 2 agents significantly inhibited cell proliferation, arrested the cell cycle, and triggered cell apoptosis. Mechanistically, MDM2 inhibitor and NMD inhibitor likely exert a synergistically through the truncated E6 protein. These results underscore the potential of employing a combination of MDM2 inhibitor and NMD inhibitor as a promising candidate for the clinical treatment of human papillomavirus-infected tumors.
Insights
Combining nonsense-mediated mRNA decay (NMD) and MDM2 inhibitors shows promise for treating human papillomavirus-infected tumors. This combination therapy effectively inhibits cancer cell growth, halts the cell cycle, and induces apoptosis in cervical cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Nonsense-mediated mRNA decay (NMD) is crucial for RNA quality control.
- The p53 pathway is a key tumor suppressor mechanism.
- The roles of NMD and p53 in cervical cancer remain unclear.
Purpose of the Study:
- To investigate the effects of NMD and MDM2 inhibitors, alone and combined, on cervical cancer cells.
- To analyze impacts on apoptosis, cell cycle, and p53 target genes.
- To explore the underlying mechanisms in human papillomavirus-18-positive HeLa cells.
Main Methods:
- Treatment of HeLa cells with an NMD inhibitor (XR-2) and an MDM2 inhibitor (SMG1 inhibitor).
- Evaluation of cell apoptosis, cell cycle progression, and p53 target gene expression.
- Assessment of combined treatment efficacy.
Main Results:
- XR-2 did not activate p53 or induce apoptosis in HeLa cells.
- SMG1 inhibitor repressed cell proliferation at high concentrations.
- Combination therapy significantly inhibited proliferation, arrested the cell cycle, and induced apoptosis.
Conclusions:
- The combination of MDM2 and NMD inhibitors demonstrates synergistic effects against cervical cancer cells.
- This combination therapy may be a promising strategy for treating human papillomavirus-related cancers.
- Synergy likely involves interaction with the truncated E6 protein.
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