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Updated: Aug 12, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile
Kate Brown1, Lisa M Miller Jenkins1, Daniel R Crooks2
1Laboratory of Cell Biology, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States.
Abstract:
TP53 is the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of TP53 mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells. Here, we investigated its effects on esophageal adenocarcinoma cells with specific p53 hot-spot mutations. NSC59984 treatment of cells reactivated p53 transcriptional regulation, inducing mitochondrial intrinsic apoptosis. Analysis of its effects on cellular metabolism demonstrated increased utilization of the pentose phosphate pathway and inhibition of glycolysis at the fructose-1,6-bisphosphate to fructose 6-phosphate junction. Furthermore, treatment of cells with NSC59984 increased reactive oxygen species production and decreased glutathione levels; these effects were enhanced by the addition of buthionine sulfoximine and inhibited by N-acetyl cysteine. We found that the effects of NSC59984 were substantially greater in cells harboring the p53 R248W mutation. Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.
Insights
The compound NSC59984 reactivates tumor suppressor p53 (encoded by TP53) in esophageal cancer cells, altering metabolism and inducing apoptosis. Its effects are more pronounced in cells with the TP53 R248W mutation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- The TP53 gene is frequently mutated in various cancers, leading to diverse gain-of-function effects.
- Targeting mutant p53 is challenging due to the variety of TP53 mutations.
- The compound NSC59984 shows promise in restoring wild-type p53 activity in cancer cells.
Purpose of the Study:
- To investigate the effects of NSC59984 on esophageal adenocarcinoma cells with specific TP53 mutations.
- To elucidate the impact of NSC59984 on p53 transcriptional regulation and cellular metabolism.
- To determine if NSC59984 efficacy varies based on specific TP53 mutation status.
Main Methods:
- Treatment of esophageal adenocarcinoma cells with NSC59984.
- Analysis of p53 transcriptional activity and apoptosis induction.
- Metabolic profiling, including pentose phosphate pathway and glycolysis assessment.
- Measurement of reactive oxygen species (ROS) and glutathione levels.
Main Results:
- NSC59984 reactivated p53 transcriptional regulation and induced mitochondrial intrinsic apoptosis.
- Metabolic analysis revealed increased pentose phosphate pathway utilization and inhibited glycolysis.
- NSC59984 increased ROS production and decreased glutathione levels, with enhanced effects when combined with buthionine sulfoximine.
- The compound demonstrated substantially greater efficacy in cells harboring the p53 R248W mutation.
Conclusions:
- NSC59984 exerts p53-dependent effects on cellular metabolism and induces apoptosis in esophageal adenocarcinoma.
- The efficacy of NSC59984 is significantly influenced by the specific TP53 mutation, particularly R248W.
- Cancer treatment strategies for TP53-driven cancers should consider individual mutational status for a patient-centric approach.
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