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Published on: July 20, 2019
The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells
Xiao Gao1,2,3, Qingwei Wang4, Ying Wang5
1East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, East China Normal University, 500 Dongchuan Road, 200241, Shanghai, China.
Abstract:
A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ 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 REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ 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 REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.
Insights
NIP30, a REGγ-proteasome inhibitor, combats chemotherapy resistance in p53-deficient cancers. It sensitizes cells to drugs by modulating REGγ activity, offering a new therapeutic strategy for drug-resistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chemotherapy resistance in p53-deficient cells is a significant clinical challenge.
- The REGγ-proteasome pathway is implicated in cancer progression.
- Targeting resistance mechanisms is crucial for improving cancer therapy outcomes.
Purpose of the Study:
- To investigate NIP30 as a regulator of the REGγ-proteasome.
- To determine NIP30's role in sensitizing p53-compromised cancer cells to chemotherapy.
- To elucidate the regulatory mechanism involving NIP30, CDC25A, and REGγ.
Main Methods:
- In vitro and in vivo experiments using cancer cell lines and mouse models.
- Biochemical assays to study protein interactions and phosphorylation.
- Analysis of TCGA cancer database for NIP30 mutations.
Main Results:
- NIP30 inhibits cancer cell growth and sensitizes p53-compromised cells to chemotherapy.
- NIP30 binds to REGγ via a phosphorylated serine-rich domain.
- CDC25A regulates NIP30 phosphorylation and REGγ activity.
- NIP30-mediated regulation of p21 was validated in vivo.
- Phosphor-NIP30 mimetics enhanced chemotherapy efficacy.
Conclusions:
- NIP30 is a novel inhibitor of the REGγ-proteasome with potential in cancer therapy.
- The CDC25A-NIP30-REGγ pathway is a key regulator in carcinogenesis.
- NIP30 offers a promising strategy for overcoming chemotherapy resistance in p53-deficient cancers.
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