Gain-of-Function Mutant TP53 R248Q Overexpressed in Epithelial Ovarian Carcinoma Alters AKT-Dependent Regulation of Intercellular Trafficking in Responses to EGFR/MDM2 Inhibitor

Autor: Zih-Yin Lai, Kai-Yun Tsai, Yung-Jen Chuang, Shing-Jyh Chang
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Mutant
Carcinoma
Ovarian Epithelial
medicine.disease_cause
combination therapy
p53R248Q overexpression
Ovarian carcinoma
Phosphorylation
Biology (General)
Spectroscopy
Mutation
Gefitinib
Proto-Oncogene Proteins c-mdm2
General Medicine
epidermal growth factor receptor (EGFR)
Tryptamines
Up-Regulation
Computer Science Applications
ErbB Receptors
Gene Expression Regulation
Neoplastic
Protein Transport
Chemistry
Gain of Function Mutation
Mdm2
Female
Signal Transduction
medicine.drug
QH301-705.5
Biology
Article
Catalysis
Inorganic Chemistry
Cell Line
Tumor
medicine
Humans
Physical and Theoretical Chemistry
Molecular Biology
Protein kinase B
QD1-999
Cell Proliferation
AKT
Organic Chemistry
Cancer
medicine.disease
Cystadenocarcinoma
Serous
Cancer research
biology.protein
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-akt
mouse double minute 2 homolog (MDM2)
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 8784, p 8784 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 16
ISSN: 1661-6596
1422-0067
Popis: As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR signaling. Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. In this study, we investigated whether the gain-of-function p53 mutation (p53R248Q) overexpression could affect EGFR-related signaling and the corresponding drug inhibition outcome in HGSOC. The targeted inhibition responses of gefitinib and JNJ-26854165, in p53R248Q-overexpressing cells, were extensively evaluated. We found that the phosphorylation of AKT increased when p53R248Q was transiently overexpressed. Immunocytochemistry analysis further showed that upon p53R248Q overexpression, several AKT-related regulatory proteins translocated in unique intracellular patterns. Subsequent analysis revealed that, under the combined inhibition of gefitinib and JNJ-26854165, the cytonuclear trafficking of EGFR and MDM2 was disrupted. Next, we analyzed the gefitinib and JNJ-26854165 responses and found differential sensitivity to the single- or combined-drug inhibitions in p53R248Q-overexpressing cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies.
Databáze: OpenAIRE
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