Curcumin rescue p53Y220C in BxPC-3 pancreatic adenocarcinomas cell line: Evidence-based on computational, biophysical, and in vivo studies.
Biochim Biophys Acta Gen Subj
; 1865(2): 129807, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-33278547
ABSTRACT
BACKGROUND:
The p53, tumor suppressor protein is inactivated upon mutation in the DNA-binding domain and the non-functional protein leads to cancers. The p53Y220C is one of the most frequently observed mutations in p53 with a scope of rescuing the protein function using small molecules.METHODS:
Using computational modeling, biophysical, and experimental cell-based studies we tried to understand the molecular basis of Curcumin as a potential small molecule to stabilize p53Y220C mutant and restore its function. The pancreatic adenocarcinomas BxPC-3 p53Y220C mutant cell line was used for cell-based assays to determine the therapeutic potential of Curcumin to restore mutant p53 to function like wild type.RESULTS:
Our results showed that the Curcumin binds p53Y220C with Kd = 3.169 ± 0.257 µM and it increases the DNA binding affinity of the mutant by 4-fold with Kd = 851.29 ± 186.27 nM. By Fluorescence, CD, and IR spectroscopy, we could characterize the secondary structural changes and stabilization of the p53Y220C DNA binding domain upon Curcumin binding. By caspase-3 and Annexin V assays, we could demonstrate that Curcumin at 3 µM to 8 µM concentration could initiate p53 mediated apoptosis in BxPC-3 cell line. Based on our experimental studies, we propose a mechanism for the activation of ATM/Chk1 kinases pathways for apoptosis and/or G2/M cell cycle arrest in the BxPC-3 cell line mediated by functionally restored p53Y220C.CONCLUSION:
The study indicated that the natural compound Curcumin could rescue mutant p53Y220C in BxPC-3 pancreatic adenocarcinomas cell line to function like wild-type and activate apoptotic pathways.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Adenocarcinoma
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Proteína Supressora de Tumor p53
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Apoptose
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Curcumina
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Gen Subj
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Índia