Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53.
Animals
Atorvastatin
/ pharmacology
Carcinogenesis
/ drug effects
Cell Line, Tumor
Disease Models, Animal
Farnesyltranstransferase
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
/ drug effects
HSP40 Heat-Shock Proteins
/ genetics
Humans
Mice
Molecular Chaperones
/ genetics
Mutant Proteins
/ genetics
Pancreas
/ metabolism
Pancreatic Neoplasms
/ drug therapy
Prenylation
/ drug effects
Proto-Oncogene Proteins p21(ras)
/ genetics
Quinolones
/ pharmacology
Tumor Suppressor Protein p53
/ genetics
DNAJA1
atorvastatin
carcinogenesis
farnesylation
mutant p53
pancreas
Journal
Molecular carcinogenesis
ISSN: 1098-2744
Titre abrégé: Mol Carcinog
Pays: United States
ID NLM: 8811105
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
25
02
2019
revised:
24
07
2019
accepted:
26
07
2019
pubmed:
10
8
2019
medline:
25
1
2020
entrez:
10
8
2019
Statut:
ppublish
Résumé
Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.
Identifiants
pubmed: 31397499
doi: 10.1002/mc.23097
pmc: PMC6800788
mid: NIHMS1044095
doi:
Substances chimiques
Dnaja1 protein, mouse
0
HSP40 Heat-Shock Proteins
0
Molecular Chaperones
0
Mutant Proteins
0
Quinolones
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
Atorvastatin
A0JWA85V8F
Farnesyltranstransferase
EC 2.5.1.29
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
tipifarnib
MAT637500A
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2052-2064Subventions
Organisme : NCI NIH HHS
ID : R01 CA164041
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA122514
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107767
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA172431
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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