| First Author | Gao X | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 3904 |
| PubMed ID | 32764536 | Mgi Jnum | J:297010 |
| Mgi Id | MGI:6468858 | Doi | 10.1038/s41467-020-17667-7 |
| Citation | Gao X, et al. (2020) The REGgamma inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells. Nat Commun 11(1):3904 |
| abstractText | A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGgamma-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGgamma via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGgamma activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGgamma mediated regulation of the REGgamma target protein p21 in vivo using p53-/- and p53/REGgamma double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGgamma-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy. |
