Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis
Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis
BACKGROUND: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently.
RESULTS: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor.
CONCLUSIONS: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.
Activating Transcription Factor 3, Animals, Calcitonin Gene-Related Peptide, Cholesterol, Dose-Response Relationship, Drug, Epoxide Hydrolases, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nervous System, Neurons, Plant Lectins, Plant Oils, Promoter Regions, Genetic, Selective Estrogen Receptor Modulators, Tamoxifen, Up-Regulation, Vitamin E, Journal Article, Research Support, Non-U.S. Gov't
74
Denk, Franziska
6bbf478a-9d9a-4b27-a6c2-b529abfe4f5c
Ramer, Leanne M.
075e95cd-7379-43a1-a34b-724fe939c278
Erskine, Erin L.K.S.
3e258d04-86b6-4b50-86b5-19bf38284493
Nassar, Mohammed A.
f7eb6257-ec39-48b9-a587-d5dd53631b0c
Bogdanov, Yury
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Signore, Massimo
82a62eb5-fdd3-44c0-8b72-2b1d37917b59
Wood, John N.
afbfb1c4-d021-4f51-88d2-9e481532b797
McMahon, Stephen B.
faa44f4a-dced-499d-9a15-d7308f8e8aff
Ramer, Matt S.
e343da09-820e-46b8-b0da-9c3e05db59e3
26 November 2015
Denk, Franziska
6bbf478a-9d9a-4b27-a6c2-b529abfe4f5c
Ramer, Leanne M.
075e95cd-7379-43a1-a34b-724fe939c278
Erskine, Erin L.K.S.
3e258d04-86b6-4b50-86b5-19bf38284493
Nassar, Mohammed A.
f7eb6257-ec39-48b9-a587-d5dd53631b0c
Bogdanov, Yury
0c970999-e191-4f1b-90d9-7bf25a5d5b4b
Signore, Massimo
82a62eb5-fdd3-44c0-8b72-2b1d37917b59
Wood, John N.
afbfb1c4-d021-4f51-88d2-9e481532b797
McMahon, Stephen B.
faa44f4a-dced-499d-9a15-d7308f8e8aff
Ramer, Matt S.
e343da09-820e-46b8-b0da-9c3e05db59e3
Denk, Franziska, Ramer, Leanne M., Erskine, Erin L.K.S., Nassar, Mohammed A., Bogdanov, Yury, Signore, Massimo, Wood, John N., McMahon, Stephen B. and Ramer, Matt S.
(2015)
Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.
Acta Neuropathologica Communications, 3, .
(doi:10.1186/s40478-015-0255-6).
Abstract
BACKGROUND: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently.
RESULTS: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor.
CONCLUSIONS: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.
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More information
Accepted/In Press date: 9 November 2015
e-pub ahead of print date: 26 November 2015
Published date: 26 November 2015
Keywords:
Activating Transcription Factor 3, Animals, Calcitonin Gene-Related Peptide, Cholesterol, Dose-Response Relationship, Drug, Epoxide Hydrolases, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nervous System, Neurons, Plant Lectins, Plant Oils, Promoter Regions, Genetic, Selective Estrogen Receptor Modulators, Tamoxifen, Up-Regulation, Vitamin E, Journal Article, Research Support, Non-U.S. Gov't
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Local EPrints ID: 417824
URI: http://eprints.soton.ac.uk/id/eprint/417824
ISSN: 2051-5960
PURE UUID: 70d9d31d-cc4d-42f2-b1bd-230f34eb4a90
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Date deposited: 15 Feb 2018 17:30
Last modified: 16 Mar 2024 04:21
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Contributors
Author:
Franziska Denk
Author:
Leanne M. Ramer
Author:
Erin L.K.S. Erskine
Author:
Mohammed A. Nassar
Author:
Massimo Signore
Author:
John N. Wood
Author:
Stephen B. McMahon
Author:
Matt S. Ramer
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