Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis

Acta Neuropathol Commun. 2015 Nov 26;3:74. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Cholesterol / metabolism*
  • Dose-Response Relationship, Drug
  • Epoxide Hydrolases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Nervous System / cytology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Plant Lectins / genetics
  • Plant Lectins / metabolism
  • Plant Oils / pharmacology
  • Promoter Regions, Genetic
  • Selective Estrogen Receptor Modulators / pharmacology*
  • Tamoxifen / pharmacology*
  • Up-Regulation / drug effects*
  • Vitamin E / pharmacology

Substances

  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Nerve Tissue Proteins
  • Plant Lectins
  • Plant Oils
  • Selective Estrogen Receptor Modulators
  • tomato lectin
  • Tamoxifen
  • Vitamin E
  • wheat germ oil
  • Cholesterol
  • Epoxide Hydrolases
  • cholesterol-5 alpha,6 alpha-epoxide hydrase
  • Calcitonin Gene-Related Peptide