Withanone binds to mortalin and abrogates mortalin-p53 complex: computational and experimental evidence.

Abstract

Mortalin binds to p53 tumor suppressor protein and sequesters it in the cytoplasm. This results in an inhibition of the transcriptional activation and control of centrosome duplication functions of p53, thus contributing to human carcinogenesis. Abrogation of mortalin-p53 interaction and reactivation of p53 function could be a valid proposition for cancer therapy. In the present study, we first investigated in silico the interaction of withanone, a withanolide with anticancer activity, with mortalin. We found that withanone could bind to mortalin in a region, earlier predicted critical for binding to p53. Cationic rhodacyanine dye, MKT-077 has also shown to bind the same region and kill cancer cells selectively. We report the molecular dynamic simulations revealing the thermodynamic and structural stability of the withanone-mortalin complexes. We also demonstrate the experimental evidence of abrogation of mortalin-p53 complex by withanone resulting in nuclear translocation and functional reactivation of p53 in human cancer cells. The present study establishes a molecular interaction basis that could be used for screening and development of anticancer drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of mortalin would further enhance the potential of such analyses to understand the molecular basis of mortalin biology and mortalin based cancer therapy.

• Authors: Abhinav Grover, Didik Priyandoko, Ran Gao, Ashutosh Shandilya, Nashi Widodo, Virendra S Bisaria, Sunil C Kaul, Renu Wadhwa, Durai Sundar
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 44 Issue 3 Pg. 496-504 (Mar 2012) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 22155302 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• HSP70 Heat-Shock Proteins
• Triterpenes
• Tumor Suppressor Protein p53
• Withanolides
• mortalin
• withanone

Topics

• Active Transport, Cell Nucleus (drug effects)
• Cell Nucleus (metabolism)
• Computational Biology
• Drug Screening Assays, Antitumor
• HSP70 Heat-Shock Proteins (metabolism)
• Humans
• Neoplasms (drug therapy, metabolism, pathology)
• Protein Binding (drug effects)
• Triterpenes (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Withania
• Withanolides