Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression

Eichelmann, AK; Mayne, GC; Chiam, K; Due, SL; Bastian, I; Butz, F; Wang, T; Sykes, PJ; Clemons, NJ; Liu, DS; Michael, MZ; Karapetis, CS; Hummel, R; Watson, DI; Hussey, DJ

Author(s): Eichelmann, AK; Mayne, GC; Chiam, K; Due, SL; Bastian, I; Butz, F; Wang, T; Sykes, PJ; Clemons, NJ; Liu, DS; Michael, MZ; Karapetis, CS; Hummel, R; Watson, DI; Hussey, DJ;
Details: Publication Year 2021-06,Volume 22,Issue #11,Page 5547
Journal Title: International Journal of Molecular Sciences
Publication Type: Research article
Abstract: TP53 gene mutations occur in 70% of oesophageal 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 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.
Keywords: Adenocarcinoma/genetics/*metabolism; Amino Acid Transport System y+/genetics/*metabolism; Antineoplastic Agents/*pharmacology; Apoptosis/drug effects/*genetics/radiation effects; Cell Line, Tumor; Cell Survival/drug effects/genetics/radiation effects; Cisplatin/pharmacology; Drug Resistance, Neoplasm/drug effects/*genetics/radiation effects; Esophageal Neoplasms/genetics/*metabolism; Estrogens/metabolism; Gene Expression Regulation, Neoplastic/drug effects/genetics/radiation effects; Gene Knockout Techniques; Gene Ontology; Glutathione/metabolism; Humans; MicroRNAs/genetics/*metabolism; Oxidative Stress/drug effects/*genetics/radiation effects; Radiation Tolerance/drug effects/genetics; Ribosomes/drug effects/metabolism; Signal Transduction/drug effects/genetics; Tumor Suppressor Protein p53/genetics/*metabolism
Department(s): Laboratory Research; Surgical Oncology
PubMed ID: 34074015
Publisher's Version: https://doi.org/10.3390/ijms22115547
Open Access at Publisher's Site: https://doi.org/10.3390/ijms22115547
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-09-24 05:52:43

Last Modified: 2026-09-24 05:53:56