Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microrna and slc7a11 expression

Ann-Kathrin Eichelmann, George C. Mayne, Karen Chiam, Steven L. Due, Isabell Bastian, Frederike Butz, Tingting Wang, Pamela J. Sykes, Nicholas J. Clemons, David S. Liu, Michael Z. Michael, Christos S. Karapetis, Richard Hummel, David I. Watson, Damian J. Hussey

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Abstract

TP53 gene mutations occur in 70% of esophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo-and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the predicted mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio-and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.

Original languageEnglish
Article number5547
Number of pages25
JournalInternational Journal of Molecular Sciences
Volume22
Issue number11
DOIs
Publication statusPublished - 1 Jun 2021
Externally publishedYes

Keywords

  • Chemoresistance
  • Esophageal cancer
  • Estrogen receptor modulator
  • MiR-27a-3p
  • MiRNA
  • Radioresistance
  • Reactive oxidative species
  • Ribosome
  • SLC7A11
  • XCT

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