Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile

Kate Brown, Lisa M.Miller Jenkins, Daniel R. Crooks, Deborah R. Surman, Sharlyn J. Mazur, Yuan Xu, Bhargav S. Arimilli, Ye Yang, Andrew N. Lane, Teresa W.M. Fan, David S. Schrump, W. Marston Linehan, R. Taylor Ripley, Ettore Appella

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number1094210
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - Jan 11 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 Brown, Jenkins, Crooks, Surman, Mazur, Xu, Arimilli, Yang, Lane, Fan, Schrump, Linehan, Ripley and Appella.

Keywords

  • NSC59984
  • gain-of-function
  • metabolism
  • mutant p53
  • p53-R248W

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile'. Together they form a unique fingerprint.

Cite this