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.
Highlights
The G protein-coupled estrogen receptor (GPER) is a seven transmembrane G protein-coupled receptor (GPCR) thatThese authors contributed : Ernesto Cortes, Dariusz Lachowski, Alistair Rice
We used immunofluorescence staining to confirm the presence of GPER and the canonical estrogen receptors alpha and beta (ER-α and ER-β) in hepatic stellate cells (HSCs) (Supplementary Fig S1)
We transfected control HSCs with constitutively active myosin-2 to increase cell contractility, and we observed significant increases in expression of both collagen-I and fibronectin (Fig. 4g), suggesting a mechanical basis to transcriptional regulation of both extracellular matrix (ECM) proteins by HSCs
Summary
The G protein-coupled estrogen receptor (GPER) is a seven transmembrane G protein-coupled receptor (GPCR) that. HSCs, like other myofibroblast-like cells [12], are highly responsive to mechanical cues, requiring a stiff microenvironment to become activated and initiate and perpetuate fibrosis They achieve this by (i) activating their contractile apparatus to apply endogenous forces to the ECM, and (ii) mechanosensing the rigidity from their surroundings [13, 14]. We report that tamoxifen induces the mechanical deactivation of HSCs via a previously unidentified mechanism that involves the GPER/RhoA/myosin axis This inhibits activation of YAP (Yes-associated protein) and durotaxis in HSCs. We show that cell contractility and ECM rigidity regulate the levels of hypoxia-inducible factor 1 alpha (HIF-1α) and lysyl oxidase (LOX) in HSCs, and that tamoxifen suppresses force-mediated regulation of both HIF-1α and LOX. HIF-1α is fundamental for cell survival in hypoxic conditions [18], as the LOX family regulates collagen crosslinking and ECM architecture and is required for hypoxia-induced metastasis
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