TY - JOUR
T1 - Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microrna and slc7a11 expression
AU - Eichelmann, Ann-Kathrin
AU - Mayne, George C.
AU - Chiam, Karen
AU - Due, Steven L.
AU - Bastian, Isabell
AU - Butz, Frederike
AU - Wang, Tingting
AU - Sykes, Pamela J.
AU - Clemons, Nicholas J.
AU - Liu, David S.
AU - Michael, Michael Z.
AU - Karapetis, Christos S.
AU - Hummel, Richard
AU - Watson, David I.
AU - Hussey, Damian J.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
KW - Chemoresistance
KW - Esophageal cancer
KW - Estrogen receptor modulator
KW - MiR-27a-3p
KW - MiRNA
KW - Radioresistance
KW - Reactive oxidative species
KW - Ribosome
KW - SLC7A11
KW - XCT
UR - http://www.scopus.com/inward/record.url?scp=85106336120&partnerID=8YFLogxK
U2 - 10.3390/ijms22115547
DO - 10.3390/ijms22115547
M3 - Article
AN - SCOPUS:85106336120
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 11
M1 - 5547
ER -
