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Published on: August 4, 2019
Small-Molecule NSC59984 Induces Mutant p53 Degradation through a ROS-ERK2-MDM2 Axis in Cancer Cells
Shengliang Zhang1,2,3,4, Lanlan Zhou1,2,3,4, Wafik S El-Deiry1,2,3,4,5
1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, Rhode Island.
Abstract:
Increased reactive oxygen species (ROS) and hyperstabilized mutant p53 are common in cancer. Hyperstabilized mutant p53 contributes to its gain of function (GOF) which confers resistance to chemotherapy and radiotherapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and antitumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells.
Implications:
An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small-molecule compounds to induce mutant p53 degradation for cancer therapy.
Insights
Targeting cancer
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mutant p53 stabilization, often due to increased reactive oxygen species (ROS), promotes cancer cell survival and chemoresistance.
- Targeting mutant p53 for degradation presents a promising therapeutic strategy in oncology.
Purpose of the Study:
- To investigate the potential of the small molecule NSC59984 in eliminating mutant p53 in cancer cells.
- To identify and characterize a novel ROS-ERK2-MDM2 axis as a vulnerability for inducing mutant p53 degradation.
Main Methods:
- Utilized the small-molecule NSC59984 to target mutant p53 degradation in cancer cells.
- Investigated the role of reactive oxygen species (ROS) and the ERK2-MDM2 pathway in mediating mutant p53 ubiquitination and degradation.
- Assessed the impact of cellular ROS levels on NSC59984 efficacy and antitumor effects.
Main Results:
- NSC59984 treatment induced constitutive phosphorylation of ERK2 via ROS, which was essential for MDM2 phosphorylation at serine-166.
- Activated MDM2 enhanced binding to mutant p53, leading to its ubiquitination and subsequent degradation.
- Higher cellular ROS levels amplified NSC59984's efficacy in degrading mutant p53 and produced greater antitumor effects.
Conclusions:
- An inducible ROS-ERK2-MDM2 axis represents a druggable vulnerability in cancers with stabilized mutant p53.
- Small molecules like NSC59984 can exploit this axis to induce mutant p53 degradation, offering a new therapeutic avenue for cancer treatment.
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