Nonsense-mediated mRNA decay inhibition synergizes with MDM2 inhibition to suppress TP53 wild-type cancer cells in p53 isoform-dependent manner

  • Cell Death Discov. 2022 Sep 30;8(1):402. doi: 10.1038/s41420-022-01190-3.
Ying Li  #  1  2  3 ,  Meng Wu  #  4 ,  Lili Zhang  3 ,  Li Wan  1 ,  Hexin Li  1 ,  Lanxin Zhang  1 ,  Gaoyuan Sun  1 ,  Wei Huang  3 ,  Junhua Zhang  3 ,  Fei Su  1 ,  Min Tang  5 ,  Fei Xiao  6  7  8
Affiliations
  • 1. Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China.
  • 2. Graduate School of Peking Union Medical College, 100730, Beijing, P. R. China.
  • 3. The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China.
  • 4. Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China.
  • 5. Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China. [email protected].
  • 6. Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China. [email protected].
  • 7. Graduate School of Peking Union Medical College, 100730, Beijing, P. R. China. [email protected].
  • 8. The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, 100730, Beijing, P. R. China. [email protected].
  • # Contributed equally.
PMID: 36180435 DOI: 10.1038/s41420-022-01190-3
Abstract

The restoration of the normal function of the tumour suppressors, such as p53, is an important strategy in tumour therapeutics. Nonsense-mediated mRNA decay (NMD) inhibition by NMD inhibitor (NMDi) upregulates functional p53 isoforms, p53β and p53γ, and activates the p53 pathway. XR-2, a novel mouse double minute 2 homolog (MDM2) inhibitor, can disrupt the interaction between p53 and MDM2, thus decreasing the MDM2-mediated degradation of p53 and increasing the p53 protein levels. However, the combined effects of these two agents have not been thoroughly explored. This study combined XR-2 and NMDi in four TP53 wild-types and four TP53-mutated Cancer cell lines. The combination of these two agents achieved significant synergistic effects on TP53 wild-type Cancer cell lines by transactivating p53 target genes, inducing Apoptosis, cell-cycle arrest and DNA damage repair. The p53β isoform induced by NMDi enhances the transactivation ability of p53α induced by XR-2, which partially explains the mechanism of the synergistic effects of XR-2 and NMDi. This study identified a combination treatment of NMDi and XR-2 which could serve as a novel Cancer therapeutic approach for MDM2-overexpressed TP53 wild-type cancers and delineated a future therapy based on the further reactivation of p53.