Small molecule nonsense mediated mRNA decay and MDM2-p53 inhibitors synergistically induce apoptosis in cervical cancer cells

Purpose: Nonsense-mediated mRNA decay (NMD) pathway and p53 pathway, which play important roles in RNA quality control and cancer suppression respectively, are tightly related to tumorigenesis, and both are promising targets for tumor therapy. However, the impact of NMD inhibitor, p53-MDM2 inhibitor, and the combination of these two agents was poorly understood in cervical cancer. Methods Cell apoptosis, cell cycle distribution, and the expression level of p53-target genes were evaluated the influence of NMD inhibitor and MDM2-p53 inhibitor treated alone or in combination on HPV-18 positive HeLa cells. Rescue experiments by E6* overexpression and RNA-seq were conducted to explore the molecular mechanism. Results The novel MDM2-p53 inhibitor, XR-2, did not activate p53 and thereby induced apoptosis in HeLa cells, whereas the NMD inhibitor (SMG1i) repressed cell proliferation at high concentrations. More importantly, the combination of these two agents significantly inhibited cell proliferation, arrest cell cycle progression, and induced cell apoptosis. Moreover, the combination treatment rose the level of hypoxia and unfolded protein response, which further increased cellular stress and led to cell apoptosis. Mechanistically, MDM2-p53 inhibitor and NMD inhibitor may act synergistically through the truncated E6 protein. Conclusion The universal synergistic effects between MDM2-p53 inhibitor and NMD inhibitor provide a potential candidate for the clinical treatment of HPV-infected tumors. However, further studies are required to elucidate the specific molecular mechanism.