Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function

Abstract

Estrogens exert their physiological and pathophysiological effects via cellular receptors, named ERα, ERβ, and G-protein coupled estrogen receptor (GPER). Estrogen-regulated physiology is tightly controlled by factors that regulate estrogen bioavailability and receptor sensitivity, while disruption of these control mechanisms can result in loss of reproductive function, cancer, cardiovascular and neurodegenerative disease, obesity, insulin resistance, endometriosis, and systemic lupus erythematosus. Restoration of estrogen physiology by modulating estrogen bioavailability or receptor activity is an effective approach for treating these pathological conditions. Therapeutic interventions that block estrogen action are employed effectively for the treatment of breast and prostate cancer as well as for precocious puberty and anovulatory infertility. Theoretically, treatments that block estrogen biosynthesis should prevent estrogen action at ERs and GPER, although drug resistance and ligand-independent receptor activation may still occur. In addition, blockade of estrogen biosynthesis does not prevent activation of estrogen receptors by naturally occurring or man-made exogenous estrogens. A more complicated scenario is provided by anti-estrogen drugs that antagonize ERs since these drugs function as GPER agonists. Based upon its association with metabolic dysregulation and advanced cancer, GPER represents a therapeutic target with promise for the treatment of several critical health concerns facing Western society. Selective ligands that specifically target GPER have been developed and may soon serve as pharmacological agents for treating human disease. Here, we review current forms of estrogen therapy and the implications that GPER holds for these therapies. We also discuss existing GPER targeted drugs, additional approaches towards developing GPER-targeted therapies and how these therapies may complement existing modalities of estrogen-targeted therapy.

GPER Agonist G-1 Disrupts Tubulin Dynamics and Potentiates Temozolomide to Impair Glioblastoma Cell Proliferation

“…In breast, GPER expression and localization were important factors in tumor progression. In normal breast tissue, triple-negative or high histological grade breast tumors, Samartzis and colleagues [ 25 ] detected GPER into the nucleus whereas the level of cytoplasmic (but not nuclear) GPER protein was associated with better overall survival in luminal tumors [ 47 , 48 ]. GPER was known to initiate non-genomic estrogen signaling when localized into the plasma or the endoplasmic reticulum membrane whereas it directly bound gene promoters and modulated transcription into the nucleus [ 26 ].…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…In addition, the expression of the same mSR in different but strictly connected tissues in the TME also offers the possibility to intervene not only on the tumorigenic process itself but also in cancer-sustaining mechanisms. Synthetic and natural compounds able to bind mSRs here presented-apart from TRPM8 and GPER, whose molecular modulators were recently and excellently reviewed [203,204]-are listed in Table 1. PaCa-2 cells (pancreatic cancer) RACK1, alpha-Actinin-1 Reduced PGRMC1 interactions with the actin cytoskeleton [225] Human granulosa/luteal cell B-cell lymphoma 2 (BCL2) pathway Increased PGRMC1 monomeric form, increased proapoptotic Harakiri (Hrk) expression [226] Due to the relative novelty of mSRs as mediators of steroid signaling, studies on mSRactive compounds here presented were limited to the pre-clinical phase.…”

“…In addition, the expression of the same mSR in different but strictly connected tissues in the TME also offers the possibility to intervene not only on the tumorigenic process itself but also in cancer-sustaining mechanisms. Synthetic and natural compounds able to bind mSRs here presented—apart from TRPM8 and GPER, whose molecular modulators were recently and excellently reviewed [ 203 , 204 ]—are listed in Table 1 .…”

Role of G Protein-Coupled Estrogen Receptor in Digestive System Carcinomas: A Minireview

“…GPER ligands may serve as novel pharmacological agents for treating human diseases. 36 Recent preclinical studies have shown that chronic administration of G1 could restore fat, glucose, and lipid homeostasis in mouse models. 37 This observation indicates that chronic GPER signaling has potential implications for the role of GPER in cancer, as metabolic syndrome is an independent risk factor for cancer.…”