Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.
Date Issued
2018-12-21
Date Acceptance
2018-11-28
Citation
Oncogene, 2018, 38, pp.2910-2922
ISSN
0950-9232
Publisher
Springer Nature [academic journals on nature.com]
Start Page
2910
End Page
2922
Journal / Book Title
Oncogene
Volume
38
Copyright Statement
© 2018 The Author(s). This article is published with open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Commission of the European Communities
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30575816
PII: 10.1038/s41388-018-0631-3
Grant Number
282051
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
HYPOXIA-INDUCIBLE FACTORS
HEPATOCELLULAR-CARCINOMA
EXTRACELLULAR-MATRIX
ACTIVATION
STIFFNESS
MECHANOTRANSDUCTION
EXPRESSION
PRESTRESS
RISK
GPER
Cell Line
Estrogens
Fibroblasts
Hepatic Stellate Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Receptors, Estrogen
Receptors, G-Protein-Coupled
Signal Transduction
Tamoxifen
Tumor Microenvironment
Cell Line
Fibroblasts
Humans
Tamoxifen
Receptors, G-Protein-Coupled
Receptors, Estrogen
Estrogens
Signal Transduction
Hypoxia-Inducible Factor 1, alpha Subunit
Hepatic Stellate Cells
Tumor Microenvironment
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2018-12-21