Wild type p53 function in p53Y220C mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
Sundar D, Yu Y, Katiyar SP, Putri JF, Dhanjal JK, Wang J, Sari AN, Kolettas E, Kaul SC, Wadhwa R
Journal of experimental & clinical cancer research : CR · 31 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- National Institute of Advanced Industrial Science and Technology
- University or hospital
- Indian Institute of Technology Delhi
Based on 2 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2019-02-26 · J Exp Clin Cancer Res · vol. 38 · issue 1 · p. 103
- Publisher
- BioMed Central
- Cited
- 41 citations · more than 95% of similar papers · 5.4× the field average
- Impact
- Top 10% most cited in its field
- References
- 61 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Phytochemicals and Medicinal Plants · Biological Research and Disease Studies · Pharmacology and Nanomedicine Research
- Keywords
- Mutant, Withaferin A, Wild type, Biology, Mutation, Mutagenesis, Withanolide, Gene, Biochemistry
- MeSH
- cell line, tumor, humans, plant extracts, antineoplastic agents, computational biology, apoptosis, molecular conformation, tumor suppressor protein p53, withanolides, molecular docking simulation
10 authors
From IN, JP, GR
- Durai SundarIndian Institute of Technology Delhi
- Yue YuNational Institute of Advanced Industrial Science and Technology
- Shashank Prakash KatiyarIndian Institute of Technology Delhi
- Jayarani Fatimah PutriNational Institute of Advanced Industrial Science and Technology
- Jaspreet Kaur DhanjalIndian Institute of Technology Delhi
- Jia WangNational Institute of Advanced Industrial Science and Technology
Abstract
Background
Tumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to selectively target mutated p53 harboring cancer cells. Restoration of wild type p53 activity in mutants using small molecules that can revert the structural changes have been considered for cancer therapeutics.
Methods
We used bioinformatics and molecular docking tools to investigate the structural changes between the wild type and mutant p53 proteins (p53V143A, p53R249S, p53R273H and p53Y220C) and explored the therapeutic potential of Withaferin A and Withanone for restoration of wild type p53 function in cancer cells. Cancer cells harboring the specific mutant p53 proteins were used for molecular assays to determine the mutant or wild type p53 functions.
Results
We found that p53V143A mutation does not show any significant structural changes and was also refractory to the binding of withanolides. p53R249S mutation critically disturbed the H-bond network and destabilized the DNA binding site. However, withanolides did not show any selective binding to either this mutant or other similar variants. p53Y220C mutation created a cavity near the site of mutation with local loss of hydrophobicity and water network, leading to functionally inactive conformation. Mutated structure could accommodate withanolides suggesting their conformational selectivity to target p53Y220C mutant. Using human cell lines containing specific p53 mutant proteins, we demonstrated that Withaferin A, Withanone and the extract rich in these withanolides caused restoration of wild type p53 function in mutant p53Y220C cells. This was associated with induction of p21WAF-1-mediated growth arrest/apoptosis.
Conclusion
The study suggested that withanolides may serve as highly potent anticancer compounds for treatment of cancers harboring a p53Y220C mutation.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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