Ashwagandha derived withanone targets TPX2-Aurora A complex: computational and experimental evidence to its anticancer activity
Grover A, Singh R, Shandilya A, Priyandoko D, Agrawal V, Bisaria VS, Wadhwa R, Kaul SC, Sundar D
PloS one · 36 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
- Government
- Ministry of Education, Culture, Sports, Science and Technology
- University or hospital
- Indian Institute of Technology Delhi
Based on 3 listed funder(s).
Publication
- Published
- 2012-01-27 · PLoS One · vol. 7 · issue 1 · p. e30890
- Publisher
- Public Library of Science
- Cited
- 58 citations · more than 87% of similar papers · 2.3× the field average
- References
- 57 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Microtubule and mitosis dynamics · Cancer-related Molecular Pathways · Protein Kinase Regulation and GTPase Signaling
- Keywords
- Aurora kinase, Cytokinesis, Mitosis, Kinase, Aurora B kinase, Aurora A kinase, Aurora inhibitor, Cell biology, Biology, Cancer cell, Docking (animal), Cell cycle, Cancer, Cell division, Cell, Biochemistry, Genetics, Medicine
- MeSH
- cell line, tumor, humans, withania, triterpenes, cell cycle proteins, microtubule-associated proteins, nuclear proteins, rna, messenger, plant extracts, antineoplastic agents, biological assay, drug screening assays, antitumor, cluster analysis, reproducibility of results, reverse transcriptase polymerase chain reaction, gene expression regulation, enzymologic, female, withanolides, molecular dynamics simulation, aurora kinases, protein serine-threonine kinases
9 authors
From IN, JP
- Abhinav GroverIndian Institute of Technology Delhi
- Rumani SinghUniversity of Tsukuba; National Institute of Advanced Industrial Science and Technology
- Ashutosh ShandilyaIndian Institute of Technology Delhi
- Didik PriyandokoUniversity of Tsukuba; National Institute of Advanced Industrial Science and Technology
- Vibhuti AgrawalIndian Institute of Technology Delhi
- Virendra Swarup BisariaIndian Institute of Technology Delhi
Abstract
Cancer is largely marked by genetic instability. Specific inhibition of individual proteins or signalling pathways that regulate genetic stability during cell division thus hold a great potential for cancer therapy. The Aurora A kinase is a Ser/Thr kinase that plays a critical role during mitosis and cytokinesis and is found upregulated in several cancer types. It is functionally regulated by its interactions with TPX2, a candidate oncogene. Aurora A inhibitors have been proposed as anticancer drugs that work by blocking its ATP binding site. This site is common to other kinases and hence these inhibitors lack specificity for Aurora A inhibition in particular, thus advocating the need of some alternative inhibition route. Previously, we identified TPX2 as a cellular target for withanone that selectively kill cancer cells. By computational approach, we found here that withanone binds to TPX2-Aurora A complex. In experiment, withanone treatment to cancer cells indeed resulted in dissociation of TPX2-Aurora A complex and disruption of mitotic spindle apparatus proposing this as a mechanism of the anticancer activity of withanone. From docking analysis, non-formation/disruption of the active TPX2-Aurora A association complex could be discerned. Our MD simulation results suggesting the thermodynamic and structural stability of TPX2-Aurora A in complex with withanone further substantiates the binding. We report a computational rationale of the ability of naturally occurring withanone to alter the kinase signalling pathway in an ATP-independent manner and experimental evidence in which withanone cause inactivation of the TPX2-Aurora A complex. The study demonstrated that TPX2-Aurora A complex is a target of withanone, a potential natural anticancer drug.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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