Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Ernesto Cortes, Dariusz Lachowski, Alistair Rice, Stephen D. Thorpe, Benjamin Robinson, Gulcen Yeldag, David A. Lee, Leo Aymar Ghemtio Wafo, Krista Rombouts, Armando E. del Río Hernández

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.
Alkuperäiskielienglanti
LehtiOncogene
Vuosikerta38
Numero16
Sivut2910–2922
Sivumäärä13
ISSN0950-9232
DOI - pysyväislinkit
TilaJulkaistu - 18 huhtikuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 317 Farmasia
  • 3122 Syöpätaudit
  • 1182 Biokemia, solu- ja molekyylibiologia

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