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Roles of TP53 gene in the development of resistance to PI3K inhibitor resistances in CRISPR-Cas9-edited lung adenocarcinoma cells
- Source :
- Cell Biology and Toxicology. 36:481-492
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- The mutation rates of tumor suppressor protein p53 gene (TP53) are high in lung adenocarcinoma and promote the development of acquired drug resistance. The present study evaluated the p53-dependent role in lung cancer cell sensitivity to PI3K-specific inhibitors, PI3K-associated inhibitors, PI3K-non-related inhibitors, and protein-based stimuli using designed p53 mutation. We found that the deletion of p53 key regions from amino acid 96 to 393 with the CRISPR-Cas9 altered multi-dimensional structure and sequencing of p53, probably leading the secondary changes in chemical structures and properties of PI3K subunit proteins or in interactions between p53 and PI3K isoform genes. The p53-dependent cell sensitivity varied among target specificities, drug chemical properties, mechanism-specific signal pathways, and drug efficacies, independently upon the size of molecules. The effects of the designed p53 mutation highly depend upon p53-involved molecular mechanisms in the cell. Our results indicate that lung cancer cell resistance to drug can develop with dynamic formations of p53 mutations changing the cell sensitivity. This may explain the real-time occurrence of cancer cell resistance to drug treatment, during which drugs may induce the new mutations of p53. Thus, it is important to dynamically monitor the formation of new mutations during the therapy and discover new drug resistance-specific targets.
- Subjects :
- 0301 basic medicine
Gene isoform
Mutation rate
Lung Neoplasms
Health, Toxicology and Mutagenesis
Cell
Adenocarcinoma of Lung
Drug resistance
Biology
Toxicology
Models, Biological
Small Molecule Libraries
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
CRISPR-Associated Protein 9
Cell Line, Tumor
medicine
Humans
Protein Isoforms
Protein Kinase Inhibitors
Gene
PI3K/AKT/mTOR pathway
Cell Proliferation
Gene Editing
Base Sequence
DNA, Neoplasm
Cell Biology
Genes, p53
medicine.disease
030104 developmental biology
medicine.anatomical_structure
A549 Cells
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Adenocarcinoma
CRISPR-Cas Systems
Subjects
Details
- ISSN :
- 15736822 and 07422091
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Cell Biology and Toxicology
- Accession number :
- edsair.doi.dedup.....d7658fe6d3e40efb71866219efef8a06